Methods for the treatment of polymorphism and cognitive impairment with GABAAα5 agonists.

Abstract

GABA A Crystalline forms of alpha5 agonists, pharmaceutical compositions and combinations comprising these crystalline forms, their use in methods for treating cognitive impairment associated with central nervous system (CNS) disorders, cognitive impairment associated with brain cancer, brain cancer itself, or Parkinson's disease psychosis, and methods for producing the crystalline forms. In another aspect, the present disclosure relates to pharmaceutical combinations comprising: a. a first pharmaceutical composition comprising the crystalline form of Compound 1 described herein; and b. one or more additional pharmaceutical compositions comprising one or more therapeutic agents selected from the group consisting of antipsychotics, memantine, SV2A inhibitors, and acetylcholinesterase inhibitors (AChEIs), or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or prodrugs of any of the foregoing.

Description

[Technical Field]

[0001] Statement of government support This invention was made with government support under grant number UH3NS101856, awarded by the National Institutes of Health (NIH), a U.S. government agency, particularly its National Institute on Aging (NIA) division. The U.S. government reserves certain rights in this invention.

[0002] Related applications This application claims the benefit and priority of U.S. Provisional Application No. 63 / 050,642, filed July 10, 2020, which is incorporated herein by reference in its entirety.

[0003] Field of Invention This invention relates to GABA A This invention relates to crystalline forms, i.e., polymorphs, of α5 agonists, pharmaceutical compositions and combinations containing these crystalline forms, and their use in methods for treating cognitive impairments associated with central nervous system (CNS) disorders, cognitive impairments associated with brain cancer, brain cancer itself, or Parkinson's disease psychiatric disorders. [Background technology]

[0004] Background of Disclosure Cognitive abilities may decline as a normal consequence of aging or as a result of central nervous system disorders. For example, a significant portion of older adults experience cognitive decline beyond what is typical for normal aging. Such age-related loss of cognitive function is clinically characterized by a progressive loss of memory, cognition, reasoning, and judgment. Age-related mild cognitive impairment (MCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD), or similar clinical classifications are associated with such age-related loss of cognitive function. Some estimates suggest that more than 16 million people in the United States alone have AAMI (Barker et al., 1995), and that 5.5 to 7 million people over 65 in the United States suffer from age-related MCI (Plassman et al., 2008).

[0005] Cognitive impairment is also associated with other central nervous system (CNS) disorders such as dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder (especially manic episodes), amyotrophic lateral sclerosis (ALS), cognitive impairment associated with cancer treatment, intellectual disability, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, Rett syndrome, obsessive-compulsive behavior, and substance addiction.

[0006] Therefore, there is a need for effective treatment of cognitive impairments associated with central nervous system (CNS) disorders, including but not limited to age-related disorders, such as age-related cognitive impairment, MCI, amnesic MCI, AAMI, ARCD, dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder (e.g., mania), amyotrophic lateral sclerosis, cognitive impairment associated with cancer treatment, intellectual disability, Parkinson's disease (PD), autism, obsessive-compulsive behavior and substance addiction, and other central nervous system (CNS) disorders associated with cognitive impairment.

[0007] Furthermore, it is considered necessary to treat cognitive impairments associated with brain cancer in patients requiring treatment, or to treat the brain cancer itself. Additionally, it is considered necessary to treat Parkinson's disease-related mental disorders in patients requiring treatment. Research has shown that GABA A The use of α5 agonists has been demonstrated to be useful in treating cognitive impairment associated with CNS disorders, cognitive impairment associated with brain cancer, brain cancer, or Parkinson's disease psychiatry. See, for example, WO2015 / 095783, WO2016 / 205739, WO2018 / 130869, WO2018 / 130868, WO2019 / 246300, and US62 / 950,886. Furthermore, the structure of compound 1, as referred to herein, is also shown. [ka] Compounds containing GABA improve cognition in individuals with cognitive impairments, for example. AIt was found to be a specific example of an α5 agonist. The synthesis procedure for compound 1 is described (see WO2019 / 246300). However, it was not previously known that compound 1 exists in any polymorphic form. [Prior art documents] [Patent Documents]

[0008] [Patent Document 1] International Publication No. 2015 / 095783 [Patent Document 2] International Publication No. 2016 / 205739 [Patent Document 3] International Publication No. 2018 / 130869 [Patent Document 4] International Publication No. 2018 / 130868 [Patent Document 5] International Publication No. 2019 / 246300 [Overview of the Initiative] [Means for solving the problem]

[0009] Summary of Disclosure This disclosure concerns structure [ka] The disclosure provides a crystalline form of compound 1 having [a certain characteristic]. In some embodiments, the crystalline form is a salt, a solvate, or a hydrate. The disclosure also provides a pharmaceutical composition comprising a crystalline form of compound 1. The disclosure also provides a process for preparing the crystalline form of compound 1, and methods for using them in the treatment of cognitive impairment associated with central nervous system (CNS) disorders or brain cancer, in the treatment of brain cancer, or in the treatment of Parkinson's disease psychiatric disorders.

[0010] In one embodiment, the present disclosure relates to the crystalline form of compound 1, wherein the crystalline form is form A.

[0011] In another aspect, the disclosure relates to the crystalline form of compound 1, wherein the crystalline form is form B.

[0012] In another aspect, the disclosure relates to the crystalline form of compound 1, wherein the crystalline form is form C.

[0013] In another aspect, the disclosure relates to the crystalline form of compound 1, wherein the crystalline form is form E.

[0014] In another aspect, the disclosure relates to the crystalline form of compound 1, wherein the crystalline form is form F.

[0015] In one embodiment, the present disclosure relates to a pharmaceutical composition comprising a crystalline form of compound 1.

[0016] In another aspect, this disclosure is: a. A first pharmaceutical composition comprising the crystalline form of compound 1 described herein, and b. One or more therapeutic agents selected from the group consisting of antipsychotics, memantine, SV2A inhibitors, and acetylcholinesterase inhibitors (AChEIs), or one or more further pharmaceutical compositions comprising any of the pharmaceutically acceptable salts, hydrates, solvates, polyforms, or prodrugs described above. Regarding combinations of pharmaceuticals that include [specific components].

[0017] In another aspect of the present disclosure, a method is provided for treating cognitive impairment associated with a CNS disorder in a subject requiring or at risk of such treatment, the method comprising the step of administering to the subject a therapeutically effective amount of a crystalline form of Compound 1 according to the present disclosure. In some embodiments, CNS disorders with cognitive impairment include, but are not limited to, age-related mild cognitive impairment, mild cognitive impairment (MCI), amnesic MCI (aMCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cognitive impairment associated with cancer treatment, intellectual disability, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, Rett syndrome, obsessive-compulsive behavior, and substance addiction.

[0018] Another aspect of the present disclosure provides a method for protecting or improving cognitive function in a subject requiring such treatment, the method comprising the step of administering to the subject a therapeutically effective amount of compound 1 of the present disclosure in crystalline form. In certain embodiments of the present disclosure, the crystalline form of compound 1 of the present disclosure is administered every 12 or 24 hours.

[0019] Another aspect of the present disclosure provides a method for treating brain cancer (including brain tumors, such as medulloblastoma) in a subject requiring treatment, the method comprising the step of administering to the subject a therapeutically effective amount of a crystalline form of compound 1 of the present disclosure.

[0020] Another aspect of the present disclosure provides a method for protecting or improving cognitive function in a subject suffering from brain cancer (including brain tumors, such as medulloblastoma), the method comprising the step of administering to the subject a therapeutically effective amount of a crystalline form of the compound of the present disclosure. In certain embodiments of the present disclosure, the crystalline form of the compound is administered every 12 or 24 hours.

[0021] Another aspect of the present disclosure provides a method for treating a Parkinson's disease psychiatric disorder in a subject requiring such treatment, the method comprising the step of administering to the subject a therapeutically effective amount of a crystalline form of the compound of the present disclosure. In a particular embodiment, the crystalline form of the compound is administered every 12 or 24 hours.

[0022] In some embodiments, the crystalline forms of the compounds according to this disclosure, as well as pharmaceutical combinations and compositions containing those crystalline forms, are intended for use as pharmaceuticals or in the manufacture of pharmaceuticals. In some embodiments, the crystalline forms of the compounds, as well as pharmaceutical combinations and compositions containing those crystalline forms, are intended for use in pharmaceuticals or in the manufacture of pharmaceuticals for treating cognitive impairments associated with CNS disorders in subjects requiring treatment for such impairments or subjects at risk of such impairments. In some embodiments, CNS disorders with cognitive impairment include, but are not limited to, age-related mild cognitive impairment, mild cognitive impairment (MCI), amnesic MCI (aMCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cognitive impairment associated with cancer treatment, intellectual disability, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, Rett syndrome, obsessive-compulsive behaviors, and substance addictions. In some embodiments, the compounds, compositions, and combinations of the Disclosure are intended for use as pharmaceuticals in the treatment of brain cancer (including brain tumors, e.g., medulloblastoma). In some embodiments, the crystalline forms, compositions, and combinations of the compounds of the Disclosure are intended for use as pharmaceuticals for the treatment of cognitive impairment associated with brain cancer (including brain tumors, e.g., medulloblastoma), or for use in the manufacture of pharmaceuticals. In some embodiments, the crystalline forms, compositions, and combinations of the compounds of the Disclosure are intended for use as pharmaceuticals in the treatment of Parkinson's disease psychiatric disorders.

[0023] Another aspect of this disclosure provides a method for producing form A, which is an anhydrous crystalline form of compound 1, a. A step of dissolving the compound in dichloromethane, b. A step of evaporating dichloromethane to produce a precipitate, and c. Step 1: Collect the precipitate to obtain the anhydrous crystalline form A of the compound. A method is provided that includes this.

[0024] In another embodiment, a method for producing form A, which is an anhydrous crystalline form of compound 1, a. A step of dissolving the compound in a first solvent at a first temperature to produce a solution. b. Adding a second solvent to the solution to form a mixture, c. If necessary, the step of cooling the mixture to a second temperature, and d. The obtained precipitate is collected to obtain form A, which is the anhydrous crystalline form of the compound. A method is provided that includes this.

[0025] In another embodiment, a method for producing form C, which is a methanolate crystalline form of compound 1, a. A step of combining compounds in methanol to form a mixture. b. Mixing the mixture for a predetermined time, c. The step of evaporating methanol from the mixture if necessary, and d. The precipitate is collected to obtain form C, which is the methanolate crystalline form of the compound. A method is provided that includes this.

[0026] In another embodiment, a method for producing form B, which is a desolvated crystalline form of compound 1, a. Steps to obtain the methylate form C of the compound, b. Heat the compound for a predetermined time to form form B, which is the desolvated crystalline form of the compound. A method is provided that includes this.

[0027] In another embodiment, a method for producing form F, which is a monohydrate crystalline form of compound 1, a. Steps to obtain the hydrochloride salt of the compound, b. Adding the hydrochloride salt of the compound to the solvent to form a mixture. c. A step of mixing the mixture for a predetermined time, d. The precipitate is collected to obtain form F, which is the monohydrate crystalline form of the compound. A method is provided that includes this.

[0028] In another embodiment, a method for producing form E, which is an anhydrous crystalline form of compound 1, a. Dissolve the compound in tetrahydrofuran at a first temperature to form a solution. b. A step of adjusting the first temperature to the second temperature to induce precipitation, c. The precipitate is collected to obtain form E, which is the anhydrous crystalline form of the compound. A method is provided that includes this. [Brief explanation of the drawing]

[0029] [Figure 1] Figure 1 shows the superimposed XRPD patterns of the anhydrous polymorphic forms of compound 1. The top diffractogram corresponds to anhydrous form A, the second from the top corresponds to desolvated form B, the third from the top corresponds to anhydrous substance D (as a mixture with form A), and the bottom corresponds to anhydrous form E.

[0030] [Figure 2] Figure 2 shows superimposed XRPD patterns of the solvated polymorphic forms of compound 1. The upper diffractogram corresponds to the methanolate form C, and the lower one corresponds to the monohydrate form F.

[0031] [Figure 3A] Figure 3 shows the thermogram of anhydrous form A. Figure 3A corresponds to the thermogravimetric analysis (TGA) curve, and Figure 3B corresponds to the differential scanning calorimetry (DSC) curve. [Figure 3B] Same as above.

[0032] [Figure 4]Figure 4 illustrates the atomic displacement ellipsoid diagram of anhydrous form A. Non-hydrogen atoms are represented by anisotropic thermal vibration ellipsoids with a 50% probability.

[0033] [Figure 5] Figure 5 shows an overlay of the experimentally obtained (top) and calculated (bottom) XRPDs for the anhydrous form A.

[0034] [Figure 6] Figure 6 illustrates the dynamic water vapor sorption isotherm for anhydrous form A.

[0035] [Figure 7] Figure 7 illustrates the indexed XRPD pattern of desolvation form B.

[0036] [Figure 8] Figure 8 shows the XRPDs of substance D initially collected after preparation (top) and substance D after 7 weeks of ambient storage (center) superimposed. The XRPD pattern of morphology A is shown for reference (bottom).

[0037] [Figure 9] Figure 9 illustrates the thermogram of substance D (as a mixture with form A). Figure 9A corresponds to the TGA curve, and Figure 9B corresponds to the DSC curve.

[0038] [Figure 10] Figure 10 illustrates the atomic displacement ellipsoid diagram of the anhydrous form E. Non-hydrogen atoms are represented by an anisotropic thermal vibration ellipsoid with a 50% probability.

[0039] [Figure 11] Figure 11 shows a superimposed XRPD of the anhydrous form E obtained experimentally (top) and calculated (bottom).

[0040] [Figure 12A]Figure 12 illustrates the thermogram of the anhydrous form E. Figure 12A corresponds to the TGA curve, and Figure 12B corresponds to the DSC curve. [Figure 12B] Same as above.

[0041] [Figure 13] Figure 13 shows an overlay of the XRPD of monohydrate form F (top) and the HCl salt of compound 1 (bottom) for reference.

[0042] [Figure 14] Figure 14 shows the indexed XRPD pattern of monohydrate morphology F.

[0043] [Figure 15A] Figure 15 illustrates the thermogram of monohydrate form F. Figure 15A corresponds to the TGA curve, and Figure 15B corresponds to the DSC curve. [Figure 15B] Same as above.

[0044] [Figure 16] Figure 16 illustrates the dynamic vapor sorption (DVS) isotherm of the monohydrate form F.

[0045] [Figure 17] Figure 17 shows the indexed XRPD pattern of metanolate morph C.

[0046] [Figure 18A] Figure 18 illustrates the thermogram of metanolate form C. Figure 18A corresponds to the TGA curve, and Figure 18B corresponds to the DSC curve. [Figure 18B] Same as above.

[0047] [Figure 19] Figure 19 shows the superimposed XRPDs of crude compound 1 (top), calculated morphology A (center), and experimentally determined morphology B (bottom). The symbol * indicates additional peaks not attributable to either morphology A or morphology B.

[0048] [Figure 20] Figure 20 is a graph showing the effect of compound 1 compared to vehicle controls using a radial maze behavior task in aged disabled rats. The graph shows the average number of errors made by aged disabled rats treated with various doses of compound 1 (2.5 mg / kg, 5 mg / kg, and 10 mg / kg).

[0049] [Figure 21] Figures 21A and 21B are graphs showing the effect of compound 1 on the Morris water maze behavior task compared to vehicle controls in aged disabled rats. Figure 21A shows the amount of time spent in the target quadrant after acute treatment with compound 1 (10 mg / kg). Figure 21B shows the amount of time spent in the target quadrant after chronic treatment (12 weeks) with compound 1 (10 mg / kg). [Modes for carrying out the invention]

[0050] Detailed explanation of disclosure definition Unless otherwise defined herein, scientific and technical terms used in this application have the meanings generally understood by those skilled in the art. In general, the nomenclature used in and relating to chemistry, cell and tissue cultures, molecular biology, cell and cancer biology, neurobiology, neuroscience, virology, immunology, microbiology, pharmacology, genetics, and protein and nucleic acid chemistry described herein is well known and commonly used in the art.

[0051] Unless otherwise indicated, the methods and techniques described herein generally follow conventional methods well known in the art, as well as conventional methods described in the various general and more specific references cited and discussed throughout this specification. See, for example, “Principles of Neural Science,” McGraw-Hill Medical, New York, NY (2000); Motulsky, “Intuitive Biostatistics,” Oxford University Press, Inc. (1995); Lodish et al., “Molecular Cell Biology, 4th ed.,” WH Freeman & Co., New York (2000); Griffiths et al., “Introduction to Genetic Analysis, 7th ed.,” WH Freeman & Co., NY (1999); and Gilbert et al., “Developmental Biology, 6th ed.,” Sinauer Associates, Inc., Sunderland, MA (2000).

[0052] The chemical terms used herein are used in accordance with the conventional usage in the art, as illustrated in "The McGraw-Hill Dictionary of Chemical Terms," ​​Parker S., Ed., McGraw-Hill, San Francisco, CA (1985).

[0053] All publications, patents, and published patent applications referenced in this application are incorporated by specific reference herein. In case of any conflict, this specification, including its specific definitions, shall prevail.

[0054] Throughout this specification, variations of the word “comprise,” “comprises,” or “comprising” are understood to mean the inclusion of a specified integer (or component) or group of integers (or components), but not the exclusion of any other integer (or component) or group of integers (or components).

[0055] The singular forms "a," "an," and "the" include the plural unless the context specifically indicates otherwise.

[0056] The term "including" is used to mean "including but not limited to these." "Including" and "including but not limited to these" are used interchangeably.

[0057] The terms "patient," "subject," or "individual" are used interchangeably and refer to either a human or a non-human animal. These terms include mammals (humans, primates, domestic animals (including cattle, pigs, etc.), companion animals (e.g., dogs, cats, etc.), and rodents (e.g., mice and rats).

[0058] "Cognitive function" or "cognitive state" refers to any higher-order intelligent brain processes or states related to learning and / or memory, including, but not limited to, attention, information acquisition, information processing, working memory, short-term memory, long-term memory, anterograde memory, retrograde memory, memory retrieval, discriminative learning, decision-making, inhibitory response control, attentional set shift, delayed reinforcement learning, reverse learning, time integration of spontaneous behavior, display of interest in the surrounding environment and self-care, processing speed, reasoning and problem-solving, and social cognition.

[0059] In humans, cognitive function can be assessed using, for example without limitation, the Clinical Global Impression Change Scale (CIBIC-plus scale); the Mini-Mental State Examination (MMSE); the Neuropsychiatric Symptom Scale (NPI); the Clinical Dementia Scale (CDR); the Cambridge Neuropsychological Test Battery (CANTAB); the Sando Geriatric Assessment (SCAG), the Buschke Multiple Choice Recollection Test (Buschke and Fuld, 1974); the Verbal Paired Associative Subtest; the Logical Memory Subtest; the Visual Recall Subtest of the Revised Wechsler Memory Scale (WMS-R) (Wechsler, 1997); the Benton Visual Recall Test or the Explicit Three-Option Forced Selection Task; or the MATRICS Consensus Neuropsychological Test Battery. Folstein et al., J Psychiatric Res 12:189-98, (1975);Robbins et al., Dementia 5:266-81, (1994);Rey, L'examen clinique en psychologie, (1964);Kluger et al., J Geriatr Psychiatry Neurol 12:168-79, (1999); see Marquis et al., 2002 and Masur et al., 1994. See also Buchanan, RW, Keefe, RSE, Umbricht, D., Green, MF, Laughren, T., and Marder, SR (2011), The FDA-NIMH-MATRICS guidelines for clinical trial design of cognitive-enhancing drugs: what do we know 5 years later? Schizophr. Bull. 37, 1209-1217.

[0060] In animal model systems, cognitive function can be assessed using a variety of conventional methods known in the art, including the use of Morris water mazes (MWMs), Barnes circular mazes, elevated radial mazes, T-mazes, or any other maze in which animals utilize spatial information. Cognitive function can also be assessed by evaluating reverse learning, out-of-dimensional set shifting, conditioned discrimination learning, and reward expectancy. Other tests known in the art can also be used to assess cognitive function, such as novel object recognition tasks and odor recognition tasks.

[0061] Cognitive function can also be assessed using imaging techniques such as positron emission tomography (PET), functional magnetic resonance imaging (fMRI), single-photon emission tomography (SPECT), or any other imaging technique capable of measuring brain function. In animals, cognitive function can also be measured by electrophysiological techniques.

[0062] "Enhancing" cognitive function refers to the effect on impaired cognitive function so that it closely resembles the function of a normal individual. Cognitive function can be enhanced to any detectable degree, but in humans, it is preferably enhanced to the point where the impaired individual can perform daily activities of normal life at a level of proficiency as close as possible to that of a normal individual or a normal individual of the same age.

[0063] In some cases, “enhancement” of cognitive function in an age-related cognitive impairment means that the impaired cognitive function is affected to such an extent that it closely resembles the function of a normal subject of the same age or a young adult subject. The cognitive function of the subject can be enhanced to any detectable degree, but in humans, it is preferably enhanced to the extent that the impaired subject can perform the daily activities of normal life at a level of proficiency as close as possible to that of a normal subject, a young adult subject, or a normal subject of the same age.

[0064] "Protection" of cognitive function refers to influencing normal or impaired cognitive function in such a way that it does not decline, does not fall below the level observed in the subject at the time of initial presentation or diagnosis, or delays such decline.

[0065] "Improvement" of cognitive function includes promoting and / or protecting cognitive function in the subject.

[0066] "Cognitive impairment" refers to cognitive function in an individual that is not as robust as expected in a normal individual. In some cases, cognitive function is reduced by approximately 5%, 10%, 30%, or more compared to the cognitive function expected in a normal individual. In some cases, "cognitive impairment" in individuals with age-related cognitive impairment refers to cognitive function in an individual that is not as robust as expected in a normal individual, a normal individual of the same age, or a young adult individual (i.e., an individual with an average score for a given age on a cognitive test).

[0067] Age-related cognitive impairment refers to cognitive impairment in older subjects that is considered to be a function of aging, and the cognitive function of these subjects is not as robust as the cognitive function expected in a normal subject of the same age, or as robust as the cognitive function expected in a young adult subject or a young adult subject. In some cases, cognitive function is reduced by approximately 5%, 10%, 30%, or more compared to the cognitive function expected in a normal subject of the same age. In some cases, cognitive function is reduced to the extent expected in a normal subject of the same age, but by approximately 5%, 10%, 30%, 50%, or more compared to the cognitive function expected in a young adult subject. Age-related impaired cognitive function may be associated with mild cognitive impairment (MCI) (including amnesic and non-amnesic MCI), age-related memory impairment (AAMI), and age-related cognitive decline (ARCD).

[0068] "Cognitive impairment" in relation to or associated with AD, or in AD, refers to cognitive function in a person that is not as robust as expected in a person who has not been diagnosed with AD using conventional methods and criteria.

[0069] Mild cognitive impairment, or MCI, is a non-age-related condition characterized by isolated memory impairment and relatively normal functional abilities, without other cognitive abnormalities. A set of diagnostic criteria for clinically characterizing MCI includes one or more of the following features: (1) memory complaints (reported by the patient, informant, or physician), (2) normal activities of daily living (ADL), (3) normal overall cognitive function, (4) abnormal memory for age (defined as a score more than 1.5 standard deviations lower than the mean for a given age), and (5) absence of indicators of dementia (as defined by the DSM-IV guidelines). Petersen et al., Srch. Neurol. 56:303-308 (1999); Petersen, "Mild cognitive impairment: Aging to Alzheimer's Disease." Oxford University Press, NY (2003). Agnosia in individuals with MCI can affect any cognitive domain or mental process, including memory, language, association, attention, perception, problem-solving, executive function, and visuospatial skills. See, for example, Winbald et al., J. Intern. Med. 256: 240-240, 2004; Meguro, Acta. Neurol. Taiwan. 15:55-57, 2008; Ellison et al., CNS Spectr. 13:66-72, 2008, Petersen, Semin. Neurol. 27:22-31, 2007. MCI is further subdivided into amnesic MCI (aMCI), which is characterized in particular by impaired (or loss of) memory, and non-amnesic MCI. MCI is defined as aMCI if memory is found to be impaired, taking into account the age and educational level of the individual. On the other hand, if the subject's memory is found to be intact for age and education, but other non-memory cognitive areas such as language, executive function, or visuospatial skills are impaired, MCI is defined as non-amnestic MCI. Both aMCI and non-amnestic MCI can be further subdivided into single-domain MCI or multi-domain MCI.aMCI-single-domain refers to a state where memory is impaired but other cognitive domains are intact. aMCI-multiple-domain refers to a state where memory and at least one other cognitive domain are impaired. Non-amnesic MCI is either single-domain or multiple-domain, depending on whether more than one non-memory cognitive domain is impaired. See, for example, Peterson and Negash, CNS Spectr. 13:45-53, 2008.

[0070] The diagnosis of MCI typically requires an objective assessment of cognitive impairment, which can be accumulated through the use of well-established neuropsychological tests, including the Mini-Mental State Examination (MMSE), the Cambridge Neuropsychological Test Battery (CANTAB), and individual tests such as the Ray Auditory Language Learning Scale (AVLT), the Logical Memory Subtest of the Revised Wechsler Memory Scale (WMS-R), and the New York University (NYU) Paragraph Recall Test. See Folstein et al., J Psychiatric Res 12:189-98 (1975); Robbins et al., Dementia 5:266-81 (1994); Kluger et al., J Geriatric Psychiatry Neurol 12:168-79 (1999).

[0071] Age-related memory impairment (AAMI) refers to a decline in memory due to aging. A patient can be considered to have AAMI if they are at least 50 years old and meet all of the following diagnostic criteria: a) the patient is aware of a decline in memory ability, b) the patient performs worse on standard memory tests than a young adult, and c) all other obvious causes of memory decline other than normal aging have been ruled out (in other words, the memory decline cannot be due to other causes such as a recent heart attack or head injury, depression, adverse drug reaction, or Alzheimer's disease).

[0072] Age-related cognitive decline (ARCD) refers to a decline in memory and cognitive abilities that is a normal consequence of aging in humans (e.g., Craik & Salthouse, 1992). This also applies to virtually all mammalian species. Age-related memory impairment refers to older adults who have objectively lower memory compared to their younger years but maintain normal cognitive function compared to their peers (Crook et al., 1986). Age-appropriate memory decline is a less derogatory term that emphasizes that these are normal developmental changes (Crook, 1993; Larrabee, 1996), not pathophysiological (Smith et al., 1991), and rarely progress to overt dementia (Youngjohn & Crook, 1993). The DSM-IV (1994) systematizes the diagnostic classification of ARCD.

[0073] "Dementia" refers to a condition characterized by severe agnosia that impairs normal daily activities. Individuals with dementia often exhibit other symptoms such as impaired judgment, personality changes, disorientation, confusion, behavioral changes, speech difficulties, and motor impairments. There are various types of dementia, including Alzheimer's disease (AD), vascular dementia, Lewy body dementia, and frontotemporal dementia.

[0074] Alzheimer's disease (AD) can be characterized by memory loss in its early stages. Later symptoms include impaired judgment, disorientation, confusion, behavioral changes, speech difficulties, and motor impairments. Histologically, AD is characterized by beta-amyloid plaques and tau protein concentrates.

[0075] Vascular dementia can be caused by a stroke. Its symptoms overlap with those of Alzheimer's disease (AD), but it does not focus on memory impairment.

[0076] Lewy body dementia can be characterized by the abnormal deposition of alpha-synuclein, which forms internal neurons in the brain. Cognitive impairment may be similar to that of Alzheimer's disease (AD), and includes impaired memory and judgment, as well as behavioral changes.

[0077] Frontotemporal dementia can be characterized by gliosis, neuronal loss, superficial spongiform degeneration in the frontal cortex and / or frontotemporal lobe, and Pick bodies. Symptoms include personality and behavioral changes, including a decline in social skills and language expression / comprehension.

[0078] Post-traumatic stress disorder (PTSD) is a disorder characterized by immediate or delayed responses to a catastrophic event, characterized by re-experiencing the trauma, mental numbness or avoidance of trauma-related stimuli, and increased arousal. Re-experiencing the event includes intrusive memories, flashbacks, nightmares, and psychological or physiological distress in response to triggers of the trauma. Such responses can lead to anxiety and can have significant chronic and acute effects on the patient's quality of life and physical and emotional health. PTSD is also associated with impaired cognitive abilities, and older individuals with PTSD exhibit a greater decline in cognitive abilities compared to control patients.

[0079] Schizophrenia is a chronic wasting disorder characterized by a range of psychopathologies, including negative symptoms such as abnormal or distorted mental representations (e.g., hallucinations, delusions), decreased motivation and reduced adaptive goal-directed behavior (e.g., anhedonia, mood flattening, anemia), and positive symptoms such as cognitive impairment. While abnormalities in the brain are suggested to underlie the broad psychopathology of schizophrenia, currently available antipsychotic medications are often ineffective in treating cognitive impairment in patients and may even worsen it.

[0080] Bipolar disorder, or BP, or manic-depressive disorder, or manic-depressive illness, refers to a chronic psychological / mood disorder that may be characterized by marked mood swings, including periods of depression and periods of euphoric mania. BP may be diagnosed by a qualified physician based on personal and medical history, a physical examination and interview. The term mania or manic period or other variations may refer to a period in which an individual exhibits some or all of the following characteristics: competitiveness, rapid speech, increased levels of activity and agitation, and a sense of inflated self-esteem, euphoria, impaired judgment, insomnia, impaired concentration and aggression.

[0081] Amyotrophic lateral sclerosis (ALS), also known as ALS, is a progressive, fatal neurodegenerative disease characterized by the degeneration of motor neurons, which are nerve cells in the central nervous system that control voluntary muscle movement. ALS may also be characterized by neuronal degeneration in the entorhinal cortex and hippocampus, memory loss, and hyperexcitability of neurons in various brain regions, including the cortex.

[0082] "Cancer treatment-related cognitive impairment" refers to cognitive impairment that develops in individuals being treated with cancer therapies such as chemotherapy (e.g., chemobrain) and radiation therapy. The cytotoxic and other adverse side effects of cancer treatments on the brain may result in cognitive impairments in functions such as memory, learning, and attention.

[0083] Parkinson's disease (PD) is a neurological disorder that may be characterized by a decrease in voluntary movement. Affected individuals may have reduced motor activity and slower voluntary movements compared to healthy individuals. Patients may have a characteristic "masked" facial appearance, a tendency to rush while walking, a hunched posture, and generalized muscle weakness. There is a typical "lead-pipe" rigidity in passive movements. Another important feature of this disease is tremor of the limbs, which occurs at rest and decreases with movement.

[0084] Parkinson's disease psychiatry affects approximately one-third of PD patients and significantly impacts their quality of life. The psychiatric disorder is characterized by hallucinations, delusions, and other sensory disturbances, including a "feeling of presence" of illusions and hallucinations. The underlying causes of psychiatric disorder in PD patients are not fully understood. However, the occurrence of cognitive impairment in PD patients has been identified as a risk factor associated with the development of psychiatric disorder (Laura B. Zahodne and Hubert H. Fernandez, Drugs Aging. 2008, 25(8), 665-682).

[0085] As used herein, “autism” refers to autism spectrum disorder characterized by neurodevelopmental disorders resulting in impaired social interaction and communication due to restricted and repetitive behaviors. “Autism spectrum disorder” is a group of developmental disorders that include autism; Asperger's syndrome; pervasive developmental disorder not otherwise specified (PDD-NOS or atypical autism); Rett syndrome; and childhood disintegrative disorder.

[0086] Intellectual disability is a generalized disorder characterized by significantly impaired cognitive function and adaptive behavioral deficits. It is often defined as an intelligence quotient (IQ) score below 70. Congenital causes are the root cause of many cases of intellectual disability. Dysfunction of neuronal connections is also considered a contributing factor (Myrrhe van Spronsen and Casper C. Hoogenraad, Curr. Neurol. Neurosci. Rep. 2010, 10, 207-214).

[0087] In some cases, intellectual disability includes, but is not limited to, Down syndrome, velocariofacial syndrome, fetal alcohol syndrome, fragile X syndrome, Klinefelter syndrome, neurofibromatosis, congenital hypothyroidism, Williams syndrome, phenylketonuria (PKU), Smith-Lemley-Opitz syndrome, Prader-Willi syndrome, Phelan-McDiarmid syndrome, Mowat-Wilson syndrome, ciliary disorders, Lowe syndrome, and siderium-type X-linked intellectual disability. Down syndrome is a disorder that involves some degree of intellectual disability, characteristic facial features, and a combination of birth defects, often including cardiac defects, many infections, vision and hearing problems, and other health problems. Fragile X syndrome is a common form of hereditary intellectual disability that occurs at a frequency of 1 in 4,000 in males and 1 in 8,000 in females. This syndrome is also characterized by developmental delay, hyperactivity, attention deficit disorder, and autism-like behaviors. There is no effective treatment for fragile X syndrome.

[0088] Obsessive-compulsive disorder ("OCD") is a mental condition most commonly characterized by intrusive, repetitive, and unnecessary thoughts (obsessions) that lead to compulsive behaviors and mental acts that an individual feels compelled to perform (compulsion). Current epidemiological data indicate that OCD is the fourth most common mental disorder in the United States. While some studies suggest a prevalence of 1–3 percent of the population, the clinically recognized prevalence of OCD is much lower, suggesting that a large number of individuals with the disorder may remain undiagnosed. Individuals with OCD are often diagnosed by a psychologist, psychiatrist, or psychoanalyst according to the diagnostic criteria of the Diagnostic and Statistical Manual of Mental Disorders, 4th edition text revision (DSM-IV-TR) (2000), including the features of obsession and compulsion.

[0089] Substance addiction (e.g., drug addiction, alcohol addiction) is a mental disorder. This addiction is not triggered instantaneously upon exposure to the substance. Rather, it requires complex neuronal adaptation that occurs over different periods ranging from hours to days to months (Kauer JA Nat. Rev. Neurosci. 2007, 8, 844-858). The path to addiction generally begins with the voluntary use of one or more controlled substances or other substances (such as narcotics, barbiturates, methamphetamine, alcohol, nicotine, and various other such substances). With prolonged and sustained use of these substances, the voluntary ability to abstain from them is impaired due to the long-term effects of use on brain function and therefore on behavior. Thus, substance addiction is generally characterized by compulsive cravings, scavenging, and use of substances that persist despite negative consequences. The craving may correspond to an underlying neurobiological change in the patient, which is likely to need to be addressed in a meaningful way if recovery is sought. Substance addiction is also often characterized by life-threatening withdrawal symptoms (e.g., alcohol, barbiturates) in some cases, and in others by substantial pathological conditions (which can include nausea, vomiting, fever, dizziness, and excessive sweating), distress, and a reduced ability to recover. Alcohol addiction, also known as alcohol dependence, is one such substance addiction. Alcohol dependence is primarily characterized by four symptoms: craving, uncontrollable behavior, physical dependence, and tolerance. These symptoms can also characterize addiction to other substances. Cravings for alcohol and other substances are often as strong as cravings for food or water. Therefore, alcoholics may continue to drink despite significant family, health, and / or legal consequences.

[0090] Brain cancer is the growth of abnormal cells in brain tissue, typically associated with the growth of malignant brain tumors. As brain tumors grow, they can compress adjacent areas of the brain, potentially halting the normal function of those areas. Brain cancer rarely spreads to other tissues outside the brain. The difference between slow-growing and rapidly growing tumors can be described using tumor grading, based on how abnormally cancer cells appear under a microscope. Brain tumors are classified according to the type of cells from which the tumor is thought to originate. Diffuse fibrous astrocytoma is the most common type of primary brain tumor in adults. These tumors are histopathologically divided into three grades of malignancy: WHO Grade II astrocytoma, WHO Grade III anaplastic astrocytoma, and WHO Grade IV glioblastoma multiforme (GBM). WHO Grade II astrocytoma is the slowest-growing diffuse astrocytoma spectrum. Astrocytomas exhibit a marked tendency to invade surrounding brain tissue and exacerbate treatment attempts at local control. These invasive capabilities are often evident in both low-grade and high-grade tumors.

[0091] Glioblastoma multiforme is the most malignant stage of astrocytoma, with most patients having a survival time of less than two years. Histologically, these tumors are characterized by high cell density, a high proliferation index, endothelial proliferation, and focal necrosis. The high proliferative nature of these lesions is likely due to numerous mitogenic factors. One of the prominent features of GBM is endothelial proliferation. Hosts and receptors for angiogenic growth factors are found in GBM.

[0092] There are biological subsets of astrocytoma, which may reflect the clinical heterogeneity observed in these tumors. These subsets include brainstem gliomas, which are a form of diffuse fibrous astrocytoma in children that often follows a malignant course. Brainstem GBM shares genetic features with adult GBM that affects younger patients. Pleomorphic xanthoastrocytoma (PXA) is a superficial, low-grade astrocytic tumor that primarily affects young adults. These tumors have an unusual histological appearance, but they are usually slow-growing tumors that are suitable for surgical treatment. However, some PXA may recur as GBM. Pilocytic astrocytoma is the most common astrocytic tumor in childhood and differs clinically and histopathologically from diffuse fibrous astrocytoma that affects adults. Pilocytic astrocytoma does not have the same genomic alterations as diffuse fibrous astrocytoma. Subependymal giant cell astrocytoma (SEGA) is a low-grade periventricular astrocytic tumor usually associated with tuberculous sclerosis (TS), and histologically identical to the so-called "candle-guttering" that lines the ventricles of TS patients. Like other neoplastic lesions in TS, these grow slowly and may resemble hamartomas more than true neoplasms. Infant fibryoplastic cerebral astrocytoma (DCAI) and fibryoplastic infantile ganglioglioma (DIGG) are large, superficial, usually cystic, benign astrocytomas that affect children 1-2 years of age.

[0093] Oligodendroglioma and oligoastrocytoma (mixed glioma) are diffuse, usually brain tumors that are most closely related clinically and biologically to diffuse fibrous astrocytoma. However, these tumors are far less common than astrocytoma and generally have a better prognosis than diffuse astrocytoma. Oligodendroglioma and oligoastrocytoma can progress to either WHO grade III undifferentiated oligodendroglioma or anaplastic oligoastrocytoma, or WHO grade IV GBM. Therefore, genetic changes leading to oligodendrogliatic tumors constitute yet another pathway to GBM.

[0094] Ependymoma is a clinically diverse group of gliomas, ranging from invasive intraventricular tumors in children to benign spinal cord tumors in adults. Transition from ependymoma to GBM is rare. Choroid plexus tumors are also a diverse group of tumors that preferentially occur in the ventricular system, ranging from invasive supratentorial intraventricular tumors in children to benign cerebellopontine angle tumors in adults. Choroid plexus tumors are occasionally reported in patients with Lie-Fraumeni syndrome and von Hippel-Lindau (VHL) disease.

[0095] Medulloblastoma is a highly malignant, primitive tumor that primarily occurs in the posterior fovea of ​​the brain in children. It is the most common malignant brain tumor in children. The most lethal subtype of medulloblastoma is GABA. A This shows high expression levels and MYC amplification of the receptor α5 subunit gene. See, for example, J Biomed Nanotechnol. 2016 Jun;12(6):1297-302.

[0096] Meningiomas are common intracranial tumors that develop in the meninges and compress the brain beneath. Meningiomas are usually benign, but some "atypical" meningiomas may recur locally, and some meningiomas are, frankly speaking, malignant and may invade or metastasize to the brain. Atypical and malignant meningiomas are less common than benign meningiomas. Schwannomas are benign tumors that develop in peripheral nerves. Schwannomas can develop in cranial nerves, particularly in the vestibular portion of the eighth cranial nerve (vestibular schwannoma, acoustic neuroma), in which case they appear as cerebellopontine angle masses. Hemangioblastomas are tumors of unknown origin that are composed of endothelial cells, pericellular cells, and so-called stromal cells. These benign tumors most frequently occur in the cerebellum and spinal cord of young adults. Multiple hemangioblastomas are characteristic of von Hippel-Lindau disease (VHL). Perivascular cell tumors (HPCs) are dural tumors that can exhibit locally invasive behavior and metastasize. The histogenesis of dura-based vascular epivascular tumors (HPCs) has long been debated, with some authors classifying them as a distinct entity and others as a subtype of meningioma.

[0097] "Treating cognitive impairment" means taking steps to improve the cognitive function of an individual with cognitive impairment so that their performance on one or more cognitive tests improves to any detectable level or prevents further decline. Preferably, after treatment of cognitive impairment, the individual's cognitive function closely resembles that of a normal individual. Treatment of cognitive impairment in humans can improve cognitive function to any detectable level, but preferably, it is sufficient to enable the impaired individual to perform daily activities of normal life at the same level of proficiency as a normal individual. In some cases, "treating cognitive impairment" means taking steps to improve the cognitive function of an individual with cognitive impairment so that their performance on one or more cognitive tests improves to any detectable level or prevents further decline. Preferably, after treatment of cognitive impairment, the individual's cognitive function closely resembles that of a normal individual. In some cases, "treating cognitive impairment" in individuals with age-related cognitive impairment refers to taking steps to improve the individual's cognitive function so that, after treatment, their cognitive function closely resembles that of a normal individual of the same age or a young adult. Beneficial or desired clinical outcomes of treatment for cognitive impairment include, but are not limited to, prevention of cognitive impairment or delay or slowing of its progression; slowing of the rate of decline in cognitive function in a person suffering from cognitive impairment; or reduction, improvement or slowing of the progression of one or more symptoms of cognitive impairment associated with CNS disorders, such as age-related cognitive impairment, mild cognitive impairment (MCI), amnesic MCI (aMCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cognitive impairment associated with cancer treatment, intellectual disability, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, Rett syndrome, obsessive-compulsive behavior, and substance addiction. Treatment of age-related cognitive impairment further includes slowing the progression of age-related cognitive impairment (including, but not limited to, MCI, ARCD, and AAMI) to dementia (e.g., AD).

[0098] "Treating brain cancer" refers to preventing brain cancer or slowing its progression. In certain embodiments, treatment includes alleviating, improving, or slowing the progression of one or more symptoms associated with brain cancer. In certain embodiments, the symptom being treated is cognitive impairment. For example, the methods and compositions of this disclosure can be used to treat cognitive impairment and / or improve cognitive function in patients with brain cancer. In some embodiments of the present invention, a method is provided for protecting or improving cognitive function in a subject having brain cancer, comprising the step of administering to the subject a therapeutically effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof, hydrate thereof, solvate thereof, polymorph thereof, isomer thereof, or a combination thereof. In some embodiments, the brain tumor is medulloblastoma.

[0099] "Administering" a compound, composition, combination, or crystalline form of a compound, or "administering" them, can be done using one of a variety of methods known to those skilled in the art. For example, a compound, composition, combination, or crystalline form of a compound can be administered intravenously, arterially, intradermally, intramuscularly, intraperitoneally, intravenously, subcutaneously, intraocularly, sublingually, orally (by ingestion), intranasally (by inhalation), intrathecally, intracerebrally, and percutaneously (by absorption, e.g., through cutaneous tubes). A compound, composition, combination, or crystalline form of a compound can also be appropriately introduced by refillable or biodegradable polymer devices or other devices, e.g., patches and pumps, or formulations that provide sustained, slow, or controlled release of the compound or drug. Administration can also be carried out, e.g., once, multiple times, and / or over one or more periods of time. In some embodiments, administration includes both direct administration, including self-administration, and indirect administration, including the act of prescribing a compound, composition, combination, or crystalline form of a compound. For example, as used herein, a physician who instructs a patient to self-administer a compound, composition, combination, or crystalline form of a compound, or who instructs another person to administer a compound, composition, combination, or crystalline form of a compound, and / or a physician who provides a prescription for a drug to a patient is administering the compound, composition, combination, or crystalline form of a compound to the patient.

[0100] Also, the appropriate method of administration for a compound, composition, combination, or crystalline form of a compound is, for example, dependent on the age of the subject, whether the subject is active or inactive at the time of administration, whether the subject has cognitive impairment at the time of administration, the degree of dysfunction, as well as the chemical and biological properties (e.g., solubility, digestibility, bioavailability, stability, and toxicity) of the compound, composition, combination, or crystalline form of the compound. In some embodiments, the compound, composition, combination, or crystalline form of the compound is administered to the subject orally, e.g., by ingestion, or intravenously, e.g., by injection. In some embodiments, the compound, composition, combination, or crystalline form of the compound that is administered orally is a sustained release formulation or a slow release formulation, or is administered using a device for such slow or sustained release.

[0101] As used herein, "α5-containing GABA A receptor agonist", "α5-containing GABA A R agonist" or "GABA A α5 receptor agonist", and other variations used herein, refer to a compound that enhances the function of the α5-containing GABA A receptor (GABA A R), i.e., a compound that increases GABAergic Cl - current. In some embodiments, as used herein, the α5-containing GABA A R agonist refers to a positive allosteric modulator that activates the activity of GABA. α5-containing GABA A receptor agonists suitable for use in the present disclosure include all forms of α5-containing GABA A receptor agonists described herein and specific α5-containing GABA A receptor agonists, as well as their hydrates, their solvates, their polymorphs, their salts (e.g., pharmaceutically acceptable salts), their isomers (e.g., stereoisomers, E / Z isomers, and tautomers), and combinations thereof.

[0102] "Antipsychotic drugs," "antipsychotic agents," "antipsychotic medications," or "antipsychotic compounds" refer to (1) typical or atypical antipsychotic drugs; (2) dopamine agonists, glutamate agonists, NMDA receptor positive allosteric modulators, glycine reuptake inhibitors, glutamate reuptake inhibitors, metabotropic glutamate receptor (mGluR) agonists or positive allosteric modulators (PAMs) (e.g., mGluR2 / 3 agonists or PAMs), glutamate receptor gluR5 positive (3) refers to drugs selected from ibuallosteric modulators (PAMs), M1 muscarinic acetylcholine receptor (mAChR) positive allosteric modulators (PAMs), histamine H3 receptor antagonists, AMPA / kainate receptor antagonists, ampakine (CX-516), glutathione prodrugs, noradrenergic agonists, serotonin receptor modulators, cholinergic agonists, cannabinoid CB1 antagonists, neurokinin 3 antagonists, neurotensin agonists, MAO B inhibitors, PDE10 inhibitors, nNOS inhibitors, neurosteroids and neurotrophic factors, alpha-7 agonists or positive allosteric modulators (PAMs), serotonin 2C agonists, and / or (3) drugs useful for treating one or more signs or symptoms of schizophrenia or bipolar disorder (especially mania).

[0103] As used herein, “typical antipsychotics” refers to conventional antipsychotics that produce antipsychotic effects as well as motor-related adverse effects associated with disorders of the dopamine system in the substantia nigra and striatum. These extrapyramidal side effects (EPS) include parkinsonism, zodiac immobility, tardive dyskinesia, and dystonia. See Baldessarini and Tarazi in Goodman & Gilman's The Pharmacological Basis of Therapeutics, 10th Edition, 2001, pp. 485–520.

[0104] As used herein, “atypical antipsychotics” refers to antipsychotics that produce antipsychotic effects with little or no EPS, and these include, but are not limited to, aripiprazole, asenapine, clozapine, iloperidone, olanzapine, lurasidone, paliperidone, quetiapine, risperidone, and ziprasidone. “Atypical” antipsychotics differ from conventional antipsychotics in their pharmacological profile. Conventional antipsychotics are primarily characterized by blockade of D2 dopamine receptors, while atypical antipsychotics are characterized by blockade of 5HT a and 5HT c Atypical antipsychotics exhibit antagonistic activity and varying degrees of receptor affinity to multiple receptors, including serotonin receptors. Often referred to as serotonin / dopamine antagonists, their higher affinity for 5HT2 receptors than for D2 receptors reflects the intriguing hypothesis that this underlies the action of “atypical” or “second-generation” antipsychotics. However, atypical antipsychotics often cause side effects, including, but are not limited to, weight gain, diabetes (e.g., type II diabetes), hyperlipidemia, QTc interval prolongation, myocarditis, sexual side effects, extrapyramidal side effects, and cataracts. Therefore, atypical antipsychotics are not a homogeneous class, considering the differences in both clinical symptom relief and the potential for inducing side effects such as those listed above. Furthermore, the common side effects of atypical antipsychotics described above often limit the dosage of antipsychotics that can be used for these medications.

[0105] In some embodiments of this disclosure, the SV2A inhibitor is levetiracetam, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer. Levetiracetam refers to the compound (2S)-2-(2-oxopyrrolidine-1-yl)butanamide (International Union of Pure and Applied Chemistry (IUPAC) name). Levetiracetam is marketed as the FDA-approved antiepileptic drug KEPPRA. Typically, the therapeutically effective dose of levetiracetam (KEPPRA) ranges from 1000 to 3000 mg / day. Levetiracetam is a widely used antiepileptic drug. Levetiracetam has been shown to directly inhibit synaptic activity and neurotransmission by binding to synaptic vesicle protein 2A (SV2A), a specific site in the CNS (see, for example, Noyer et al. 1995; Fuks et al. 2003; Lynch et al. 2004; Gillard et al. 2006), thereby inhibiting presynaptic neurotransmitter release (Yang et al., 2007).

[0106] In some embodiments of this disclosure, the SV2A inhibitor is brivalacetam (marketed under the name BRIVIAC), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer. Brivalacetam refers to the compound (2S)-2-[(4R)-2-oxo-4-propylpyrrolidine-1-yl]butanamide (IUPAC name). Brivalacetam has anticonvulsant activity and binds to SV2A in the brain.

[0107] In some embodiments of this disclosure, the SV2A inhibitor is celetracetam, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer. Celetracetam refers to the compound (2S)-2-[(4S)-4-(2,2-difluoroethenyl)-2-oxopyrrolidine-1-yl]butanamide (IUPAC name). Celetracetam is an antiepileptic agent that binds to SV2A in the brain.

[0108] Various studies have shown that SV2A inhibitors, compounds that bind to SV2A and reduce synaptic function by decreasing presynaptic vesicle release (see, for example, Noyer et al. 1995, Fuks et al. 2003, Lynch et al. 2004, Gillard et al. 2006, Custer et al., 2006, Smedt et al., 2007, Yang et al., 2007, Meehan, "Levetiracetam has an activity-dependent effect on inhibitory transmission," Epilepsia, 2012 Jan 31, and Example 8 of WO2001 / 62726 (all of which are incorporated herein by special reference)), may be useful in treating cognitive impairment associated with CNS disorders, within a narrow range of low doses. For example, international patent applications PCT / US2009 / 005647 (publication number WO2010 / 044878), international patent applications PCT / US2011 / 024256 (publication number WO2011 / 100373), international patent applications PCT / US2012 / 024556 (publication number WO2012 / 109491), and international patent applications PCT / US2013 / 070144 (publication number WO2014 / 0785 See also International Patent Application No. 68), International Patent Application PCT / US2014 / 029170 (Publication No. WO2014 / 144663), International Patent Application PCT / US2014 / 029362 (Publication No. WO2014 / 144801), and International Patent Application PCT / US2016 / 033567 (Publication No. WO2016 / 191288) (all of which are incorporated herein by special reference).

[0109] Memantine is 3,5-dimethyladamantan-1-amine or 3,5-dimethyltricyclo[3.3.1.1 3,7It is chemically known as decane-1-amine and is a moderately affinity, non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. Trademark names for memantine include Axura® and Akatinol® (Merz), Namenda® (Forest Laboratories), Ebixa® and Abixa® (Lundbeck), and Memox® (Unipharm). Memantine is approved in the United States for the treatment of moderate to severe Alzheimer's disease (AD) at a maximum dose of 28 mg / day. Derivatives or analogs of memantine, including compounds structurally or chemically similar to memantine, are also useful in this disclosure. Such derivatives or analogs of memantine include, but are not limited to, compounds disclosed in U.S. Patent Nos. 3,391,142; 4,122,193; 4,273,774 and 5,061,703; U.S. Patent Publications US20040087658, US20050113458, US20060205822, US20090081259, US20090124659 and US20100227852; European Patent Publication EP2260839A2; European Patent EP1682109B1; and PCT Publication WO2005079779, all of which are incorporated herein by reference. Memantine, as used in this disclosure, includes memantine and its derivatives and analogs, as well as their hydrates, polymorphs, prodrugs, salts, and solvates. Memantine, as used herein, also includes compositions comprising memantine or its derivatives or analogs, or pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or prodrugs, in which case the composition optionally further comprises at least one further therapeutic agent (such as a therapeutic agent useful for treating CNS disorders or associated cognitive impairments). In some embodiments, a memantine composition suitable for use in this disclosure comprises memantine and a second therapeutic agent which is donepezil (trade name ARICEPT).

[0110] As used herein, “acetylcholinesterase inhibitor” or “AChEI” refers to a drug that increases the concentration and duration of acetylcholine, primarily at brain synapses or neuromuscular junctions, by inhibiting the ability of the cholinesterase enzyme to break down the neurotransmitter acetylcholine. Suitable AChEIs for use in this application may include, for example, subcategories of (i) reversible non-competitive inhibitors or reversible competitive inhibitors, (ii) irreversible inhibitors, and (iii) quasi-irreversible inhibitors. ARICEPT (donepezil) is an example of an AChEI. Other non-limiting examples include rivastigmine, galantamine (RAZADYNE), and amvenonium (MYTELASE).

[0111] As used herein, the term “simultaneous administration” refers to α5-containing GABA A Receptor agonists (e.g., α5-containing GABA) A This may mean that a receptor-positive allosteric modulator) or its crystalline form, and a second therapeutic agent (e.g., an antipsychotic, memantine, or AChEI), or a pharmaceutically acceptable salt thereof, their hydrate, their solvate, or their polymorph, are administered at time intervals not exceeding about 15 minutes, and in some embodiments, at time intervals not exceeding about 10 minutes. When the drugs are administered simultaneously, α5-containing GABA A Receptor agonists (e.g., α5-containing GABA) A Receptor-positive allosteric modulators), or their crystalline forms, and a second therapeutic agent (e.g., antipsychotics, memantine, or AChEI), or their salts, hydrates, solvates, or polymorphs, are used in the same dose (e.g., α5-containing GABA). A Receptor agonists (e.g., α5-containing GABA) A A unit dosage form containing both a receptor-positive allosteric modulator and a second therapeutic agent (e.g., an antipsychotic, memantine, or AChEI), or separate doses (e.g., α5-containing GABA). A Receptor agonists (e.g., α5-containing GABA) AA receptor-positive allosteric modulator) or a salt thereof, its hydrate, its solvate, or its polymorph may be contained in one dosage form, and a second therapeutic agent (e.g., an antipsychotic, memantine, or AChEI) or a salt thereof, its hydrate, its solvate, or its polymorph may be contained in another dosage form.

[0112] As used herein, the term “sequential administration” refers to α5-containing GABA A Receptor agonists (e.g., α5-containing GABA) A This means that a receptor-positive allosteric modulator (α5) or its crystalline form, and a second therapeutic agent (e.g., an antipsychotic, memantine, or AChEI), or pharmaceutically acceptable salts thereof, their hydrates, their solvates, or their polymorphs, are administered at time intervals not exceeding about 15 minutes, in some embodiments at time intervals not exceeding about 1 hour, or at time intervals of up to 12 to 24 hours. A Receptor agonists (e.g., α5-containing GABA) A Either a receptor-positive allosteric modulator, or its crystalline form, or a second therapeutic agent (e.g., an antipsychotic, memantine, or AChEI) may be administered first. α5-containing GABA for sequential administration. A Receptor agonists (e.g., α5-containing GABA) A A receptor-positive allosteric modulator), or its crystalline form, and a second therapeutic agent (e.g., an antipsychotic, memantine, or AChEI), or their salts, their hydrates, their solvents, or their polymorphs, may be contained in separate dosage forms, or, if necessary, in the same container or packaging.

[0113] The "therapeutic effective dose" of a drug or medication is the amount of the drug or medication that, when administered to a subject, produces the intended therapeutic effect, e.g., improvement of cognitive function, in the subject, e.g., a patient with cognitive impairment associated with CNS disorder. The complete therapeutic effect may not necessarily occur with a single dose, but may only occur after a series of doses. Therefore, the therapeutic effective dose may be administered in one or more doses. The exact effective dose required for a subject depends, for example, the subject's size, health status and age, the nature and severity of the cognitive impairment or other symptoms of CNS disorder (e.g., age-related cognitive impairment, mild cognitive impairment (MCI), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, ALS, cognitive impairment associated with cancer treatment, intellectual disability, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, Rett syndrome, obsessive-compulsive behavior, and substance addiction), the therapeutic agent or combination of therapeutic agents selected for administration, and the mode of administration. Those skilled in the art can easily determine the effective amount for a given situation through standard experiments.

[0114] The term "combination drug" refers to a drug product containing two active agents together (i.e., in one formulation) or separately (i.e., as two separate formulations). The active agents in a combination drug can be administered simultaneously or sequentially. The two active agents can be administered using the same method, i.e., intraperitoneally, orally, or by different methods. For example, one drug can be administered using one method, e.g., orally, and the other can be administered using a different method, e.g., intraperitoneally.

[0115] Various CNS disorders associated with cognitive impairment (e.g., age-related cognitive impairment (including age-related mild cognitive impairment), mild cognitive impairment (MCI), amnesic MCI (aMCI), age-related memory impairment (AAMI), age-related cognitive decline (ARCD), dementia, Alzheimer's disease (AD), prodromal AD, post-traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cognitive impairment associated with cancer treatment, intellectual disability, Parkinson's disease (PD), autism spectrum disorder, fragile X disorder, Rett syndrome, obsessive-compulsive behavior, and substance addiction) may have diverse etiologies. However, the symptoms of cognitive impairment in each of the above disorders may have overlapping causes. Therefore, a composition or method of treatment for cognitive impairment associated with one CNS disorder may also be able to treat cognitive impairment associated with other CNS disorders.

[0116] As used herein, the term “crystalline form” refers to the anhydrous, hydrate, solvate, or salt form of Compound 1.

[0117] As used herein, the term “hydrate” refers to a combination of water and the compound according to this disclosure, wherein water is absorbed, adsorbed, or contained within the crystal lattice of the substrate compound.

[0118] As used herein, the term “solvate” refers to a combination of a solvent and a compound according to this disclosure, wherein the solvate is absorbed, adsorbed, or contained within the crystal lattice of the compound.

[0119] As used herein, the term “anhydrous” refers to a form of the compound according to this disclosure that is completely solvent-free, for example, in which no solvent molecules are contained within the crystal lattice of the compound.

[0120] As used herein, the term “polymorph” refers to different crystalline forms and molecular forms of other solid states (including pseudopolymorphs) of the same compound, such as hydrates (e.g., bound water present in the crystalline structure) and solvates (e.g., bound solvents other than water). Different crystalline polymorphs have different crystalline structures due to different molecular packing within their lattices. This results in different crystal symmetries and / or unit cell parameters, which directly affect their physical properties, such as the X-ray diffraction characteristics of the crystal or powder. For example, different polymorphs generally diffract at different sets of angles, resulting in different values ​​for their intensities. Thus, powder X-ray diffraction can be used to identify or distinguish solid states containing different polymorphs, or more than one polymorph, in a reproducible and reliable manner. Crystallographic polymorphisms are of interest to the pharmaceutical industry and, in particular, to those involved in the development of suitable dosage forms. If the polymorphisms are not kept constant during clinical or stability studies, the very dosage form used or studied may not be comparable from lot to lot. When a compound is used in clinical studies or in products, the presence of impurities may lead to undesirable toxicological effects; therefore, it is desirable to have a process for producing the compound in high purity with selected polymorphic forms. Certain polymorphic forms may exhibit improved thermodynamic stability or may be easier to produce in large quantities with high purity, and are therefore more suitable for inclusion in pharmaceutical formulations. Certain polymorphic forms may exhibit other beneficial physical properties, such as no tendency to absorb moisture, improved solubility, and improved dissolution rates due to different lattice energies. Compounds disclosed herein

[0121] In some aspects, this disclosure is structure [ka] This invention relates to compound 1 having GABA, as well as its amorphous form, salt form, anhydrous form, and solvated form. Compound 1 is GABA AIt is an α5 positive allosteric modulator and is useful for treating cognitive impairment associated with CNS disorders in subjects requiring or at risk of such treatment, and / or slowing the progression of cognitive impairment in subjects requiring or at risk of such treatment, and / or reducing the rate of cognitive decline in subjects requiring or at risk of such treatment (see WO2019 / 246300). Compound 1 is also useful for treating brain cancer, brain cancer-related cognitive impairment, and Parkinson's disease psychiatry.

[0122] In some cases, it is preferable to use the amorphous form of compound 1 to improve solubility and bioavailability properties. In other cases, it is preferable to use the crystalline form of compound 1 to improve stability.

[0123] Compound 1 has been found to exist in at least five crystalline polymorphic forms (i.e., form A, form B, form C, substance D, form E, and form F). In some embodiments, this disclosure relates to the crystalline forms of Compound 1, where the crystalline forms correspond to form A, form B, form C, substance D, form E, or form F, or any mixture thereof. In some embodiments, this disclosure relates to the anhydrous crystalline form of Compound 1, where the crystalline forms correspond to form A, form B, substance D, or form E. In some embodiments, this disclosure relates to the solvated crystalline form of Compound 1, where the crystalline form corresponds to form C or form F. In certain such embodiments, the solvated crystalline form of Compound 1 is a methanolate or a hydrate.

[0124] The salt form of compound 1 is also intended by this disclosure. pK of compound 1 (free base) aThe value is 1.16 ± 0.04. Therefore, the salt form can be achieved by reacting the free base form of compound 1 with a suitable strong acid, such as hydrochloric acid, sulfuric acid, benzenesulfonic acid, ethane-1,2-disulfonic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, and toluenesulfonic acid. In some embodiments, this disclosure relates to the crystalline salt form of compound 1, where the salt is a hydrochloride, besilate, mesilate, napadisylate, napsylate, sulfate, or tosilate. Further salt forms can be achieved using other strong acids known to those skilled in the art.

[0125] In some embodiments, the crystalline form of compound 1 is morphology A, and it exhibits an XRPD pattern including at least one peak selected from 3.0 and 21.0 degrees 2θ ± 0.2 degrees 2θ.

[0126] In some embodiments, the crystalline form of compound 1 is morphology A, and it exhibits an XRPD pattern further including at least one additional peak selected from the group consisting of 9.1, 10.7, 13.8, 22.0, 23.1, 23.9, 24.4, and 27.1 degrees 2θ ± 0.2 degrees 2θ.

[0127] In some embodiments, the disclosure provides a crystalline form of compound 1, the crystalline form being anhydrous. In some embodiments, the crystalline form of compound 1 is form A. In some embodiments, crystalline form A is a. The X-ray powder diffraction (XRPD) pattern is essentially shown in Figure 5. b. X-ray diffraction space group of a single crystal of C2 / c, c. Parameters: a=58.1415(14)Å, b=4.03974(8)Å, c=17.1204(3)Å, α=90°, β=90.261(2)°, γ=90°, V=4021.15(14)Å 3 X-ray diffraction unit cell of a single crystal having d. The differential scanning calorimetry (DSC) curves shown in Figure 3B, and e. Differential scanning calorimetry (DSC) curves exhibiting exothermic properties starting at approximately 207°C. Characterized by one or more of these.

[0128] In some embodiments, crystalline form A is a. The X-ray powder diffraction (XRPD) pattern is essentially shown in Figure 5. b. X-ray diffraction space group of a single crystal of C2 / c, c. Parameters: a=58.1415(14)Å, b=4.03974(8)Å, c=17.1204(3)Å, α=90°, β=90.261(2)°, γ=90°, V=4021.15(14)Å 3 X-ray diffraction unit cell of a single crystal having d. The differential scanning calorimetry (DSC) curves shown in Figure 3B, and e. Differential scanning calorimetry (DSC) curves exhibiting exothermic properties starting at approximately 207°C. Characterized by two or more of these.

[0129] In some embodiments, crystalline form A is a. The X-ray powder diffraction (XRPD) pattern is essentially shown in Figure 5. b. X-ray diffraction space group of a single crystal of C2 / c, c. Parameters: a=58.1415(14)Å, b=4.03974(8)Å, c=17.1204(3)Å, α=90°, β=90.261(2)°, γ=90°, V=4021.15(14)Å 3 X-ray diffraction unit cell of a single crystal having d. The differential scanning calorimetry (DSC) curves shown in Figure 3B, and e. Differential scanning calorimetry (DSC) curves exhibiting exothermic properties starting at approximately 207°C. It is characterized by three or more of the following.

[0130] In some embodiments, crystalline form A has the following characteristics: a. The X-ray powder diffraction (XRPD) pattern is essentially shown in Figure 5. b. X-ray diffraction space group of a single crystal of C2 / c, c. Parameters: a=58.1415(14)Å, b=4.03974(8)Å, c=17.1204(3)Å, α=90°, β=90.261(2)°, γ=90°, V=4021.15(14)Å 3 X-ray diffraction unit cell of a single crystal having d. The differential scanning calorimetry (DSC) curves shown in Figure 3B, and e. Differential scanning calorimetry (DSC) curves exhibiting exothermic properties starting at approximately 207°C. It is characterized by:

[0131] In one or more embodiments, crystalline form A of compound 1 is characterized by differential scanning calorimetry (DSC) having exothermic reactions between 200°C and 215°C. For example, form A of compound 1 may be characterized by differential scanning calorimetry (DSC) having exothermic reactions at 200°C, 201°C, 202°C, 203°C, 204°C, 205°C, 206°C, 207°C, 208°C, 209°C, 210°C, 211°C, 212°C, 213°C, 214°C, or 215°C. For example, morphology A of compound 1 may be characterized by differential scanning calorimetry (DSC) having exothermic reactions at approximately 200°C, 201°C, 202°C, 203°C, 204°C, 205°C, 206°C, 207°C, 208°C, 209°C, 210°C, 211°C, 212°C, 213°C, 214°C, or 215°C. In some embodiments, crystalline morphology A of compound 1 is characterized by differential scanning calorimetry (DSC) having exothermic reactions at approximately 207°C.

[0132] In some embodiments, the crystalline form of compound 1 is form B, and it exhibits an XRPD pattern containing at least one peak selected from 13.0 and 15.3 degrees 2θ ± 0.2 degrees 2θ.

[0133] In some embodiments, the crystalline form of compound 1 is form B, and it exhibits an XRPD pattern further including at least one additional peak selected from the group consisting of 7.0, 9.3, 10.2, 10.4, 12.5, 13.6, 14.0, 22.0, 23.0, 23.6, and 27.3 degrees 2θ ± 0.2 degrees 2θ.

[0134] In some embodiments, the disclosure provides a crystalline form of compound 1, which is desolvated. In some embodiments, the crystalline form of compound 1 is form B. In some embodiments, crystalline form B is a. The X-ray powder diffraction (XRPD) pattern is substantially shown in Figure 7. b. Unit cell of X-ray diffraction of monoclinic single crystals, c. Approximately 497Å 3 The X-ray diffraction formula per unit volume of a single crystal, and d. Differential scanning calorimetry (DSC) curve with exothermic properties starting at approximately 190°C. Characterized by one or more of these.

[0135] In some embodiments, crystalline form B is a. The X-ray powder diffraction (XRPD) pattern is substantially shown in Figure 7. b. Unit cell of X-ray diffraction of monoclinic single crystals, c. Approximately 497Å 3 The X-ray diffraction formula per unit volume of a single crystal, and d. Differential scanning calorimetry (DSC) curve with exothermic properties starting at approximately 190°C. Characterized by two or more of these.

[0136] In some embodiments, crystalline form B is a. The X-ray powder diffraction (XRPD) pattern is substantially shown in Figure 7. b. Unit cell of X-ray diffraction of monoclinic single crystals, c. Approximately 497Å 3 The X-ray diffraction formula per unit volume of a single crystal, and d. Differential scanning calorimetry (DSC) curve with exothermic properties starting at approximately 190°C. It is characterized by three or more of the following.

[0137] In some embodiments, crystalline form B is a. The X-ray powder diffraction (XRPD) pattern is substantially shown in Figure 7. b. Unit cell of X-ray diffraction of monoclinic single crystals, c. Approximately 497Å 3 The X-ray diffraction formula per unit volume of a single crystal, and d. Differential scanning calorimetry (DSC) curve with exothermic properties starting at approximately 190°C. It is characterized by:

[0138] In one or more embodiments, the crystalline form B of compound 1 is 495 Å. 3 ~500Å 3 It is characterized by the X-ray diffraction formula per unit volume of the single crystal. For example, form B of compound 1 is 495 Å. 3 , 496Å 3 , 497Å 3 , 498Å 3 , 499Å 3 , or 500 Å 3 It may also be characterized by the X-ray diffraction formula per unit volume of the single crystal. In some embodiments, the crystalline form B of compound 1 is characterized by the X-ray diffraction formula per unit volume of the single crystal at 497°C.

[0139] In one or more embodiments, crystalline form B of compound 1 is characterized by differential scanning calorimetry (DSC) having exothermic reactions between 185°C and 195°C. For example, form B of compound 1 may be characterized by differential scanning calorimetry (DSC) having exothermic reactions at 185°C, 186°C, 187°C, 188°C, 189°C, 190°C, 191°C, 192°C, 193°C, 194°C, and 195°C. For example, form B of compound 1 may be characterized by differential scanning calorimetry (DSC) having exothermic reactions at approximately 185°C, approximately 186°C, approximately 187°C, approximately 188°C, approximately 189°C, approximately 190°C, approximately 191°C, approximately 192°C, approximately 193°C, approximately 194°C, and approximately 195°C. In some embodiments, the crystalline form B of compound 1 is characterized by differential scanning calorimetry (DSC) which has an exothermic reaction of 190°C.

[0140] In some embodiments, the crystalline form of compound 1 is morphology C, and it exhibits an XRPD pattern containing at least one peak selected from 8.5 and 18.9 degrees 2θ ± 0.2 degrees 2θ.

[0141] In some embodiments, the crystalline form of compound 1 is morphology C, and it exhibits an XRPD pattern further including at least one additional peak selected from the group consisting of 7.1, 9.4, 10.3, 12.3, 12.5, 14.2, 20.7, 22.1, 23.2, 23.7, 24.0, and 26.4 degrees 2θ ± 0.2 degrees 2θ.

[0142] In some embodiments, the disclosure provides a crystalline form of compound 1, the crystalline form being solvated. In some embodiments, the solvated crystalline form of compound 1 is a methanolate. In some embodiments, the solvated crystalline form of compound 1 is form C. In some embodiments, crystalline form C is a. The X-ray powder diffraction (XRPD) pattern is substantially shown in Figure 17. b. Unit cell of X-ray diffraction of monoclinic single crystals, c. Approximately 544Å 3 X-ray diffraction formula per unit volume of a single crystal, d. The differential scanning calorimetry (DSC) curves, essentially shown in Figure 18B, and e. Differential scanning calorimetry (DSC) curves with exothermic properties starting at approximately 190°C. Characterized by one or more of these.

[0143] In some embodiments, the crystalline form C is a. The X-ray powder diffraction (XRPD) pattern is substantially shown in Figure 17. b. Unit cell of X-ray diffraction of monoclinic single crystals, c. Approximately 544Å 3 X-ray diffraction formula per unit volume of a single crystal, d. The differential scanning calorimetry (DSC) curves, essentially shown in Figure 18B, and e. Differential scanning calorimetry (DSC) curves with exothermic properties starting at approximately 190°C. Characterized by two or more of these.

[0144] In some embodiments, the crystalline form C is a. The X-ray powder diffraction (XRPD) pattern is substantially shown in Figure 17. b. Unit cell of X-ray diffraction of monoclinic single crystals, c. Approximately 544Å 3 X-ray diffraction formula per unit volume of a single crystal, d. The differential scanning calorimetry (DSC) curves, essentially shown in Figure 18B, and e. Differential scanning calorimetry (DSC) curves with exothermic properties starting at approximately 190°C. It is characterized by three or more of the following.

[0145] In some embodiments, the crystalline form C is a. The X-ray powder diffraction (XRPD) pattern is substantially shown in Figure 17. b. Unit cell of X-ray diffraction of monoclinic single crystals, c. Approximately 544Å 3 X-ray diffraction formula per unit volume of a single crystal, d. The differential scanning calorimetry (DSC) curves, essentially shown in Figure 18B, and e. Differential scanning calorimetry (DSC) curves with exothermic properties starting at approximately 190°C. It is characterized by four or more of the following.

[0146] In some embodiments, the crystalline form C is a. The X-ray powder diffraction (XRPD) pattern is substantially shown in Figure 17. b. Unit cell of X-ray diffraction of monoclinic single crystals, c. Approximately 544Å 3 X-ray diffraction formula per unit volume of a single crystal, d. The differential scanning calorimetry (DSC) curves, essentially shown in Figure 18B, and e. Differential scanning calorimetry (DSC) curves with exothermic properties starting at approximately 190°C. It is characterized by:

[0147] In one or more embodiments, the crystalline form C of compound 1 is 495 Å. 3 ~505Å 3 It is characterized by the X-ray diffraction formula per unit volume of the single crystal. For example, morphology C of compound 1 is 495 Å. 3 , 496Å 3 , 497Å 3 , 498Å 3 , 499Å 3 , 500Å 3 , 501 Å 3 , 502Å 3 , 503Å 3 , 504Å 3 , or 505 Å 3 It may also be characterized by the X-ray diffraction formula per unit volume of the single crystal. In some embodiments, the crystalline form C of compound 1 is 497 Å. 3 It is characterized by the X-ray diffraction formula per unit volume of the single crystal.

[0148] In one or more embodiments, the crystalline form C of compound 1 is characterized by differential scanning calorimetry (DSC) having exothermic reactions between 185°C and 195°C. For example, form C of compound 1 may be characterized by differential scanning calorimetry (DSC) having exothermic reactions at 185°C, 186°C, 187°C, 188°C, 189°C, 190°C, 191°C, 192°C, 193°C, 194°C, or 195°C. For example, form C of compound 1 may be characterized by differential scanning calorimetry (DSC) having exothermic reactions at approximately 185°C, approximately 186°C, approximately 187°C, approximately 188°C, approximately 189°C, approximately 190°C, approximately 191°C, approximately 192°C, approximately 193°C, approximately 194°C, or approximately 195°C. In some embodiments, the crystalline form C of compound 1 is characterized by differential scanning calorimetry (DSC) which has an exothermic reaction of 190°C.

[0149] In some embodiments, the crystalline form of compound 1 is morphology E, and it exhibits an XRPD pattern including at least one peak selected from the group consisting of 11.4, 18.1, and 21.6 degrees 2θ ± 0.2 degrees 2θ.

[0150] In some embodiments, the crystalline form of compound 1 is morphology E, and it exhibits an XRPD pattern further including at least one additional peak selected from the group consisting of 7.2, 22.0, 23.0, 24.2, 25.0, and 26.6 degrees 2θ ± 0.2 degrees 2θ.

[0151] In some embodiments, the present disclosure provides a crystalline form of compound 1, the crystalline form being anhydrous. In some embodiments, the solvated crystalline form of compound 1 is form E. In some embodiments, crystalline form E is a. The X-ray powder diffraction (XRPD) pattern is substantially shown in Figure 11. b. X-ray diffraction space group of single crystals of P21 / n, c. Parameters: a=11.83974(13)Å, b=23.5195(2)Å, c=14.48807(17)Å, α=90°, β=101.5333(11)°, γ=90°, V=3952.96(7)Å 3 X-ray diffraction unit cell of a single crystal having d. The differential scanning calorimetry (DSC) curves shown in Figure 12B, and e. Differential scanning calorimetry (DSC) curves exhibiting exothermic properties starting at approximately 201°C. Characterized by one or more of these.

[0152] In some embodiments, the solvated crystalline form of compound 1 is form E. In some embodiments, crystalline form E is a. The X-ray powder diffraction (XRPD) pattern is substantially shown in Figure 11. b. X-ray diffraction space group of single crystals of P21 / n, c. Parameters: a=11.83974(13)Å, b=23.5195(2)Å, c=14.48807(17)Å, α=90°, β=101.5333(11)°, γ=90°, V=3952.96(7)Å 3 X-ray diffraction unit cell of a single crystal having d. The differential scanning calorimetry (DSC) curves shown in Figure 12B, and e. Differential scanning calorimetry (DSC) curves exhibiting exothermic properties starting at approximately 201°C. Characterized by two or more of these.

[0153] In some embodiments, the solvated crystalline form of compound 1 is form E. In some embodiments, crystalline form E is a. The X-ray powder diffraction (XRPD) pattern is substantially shown in Figure 11. b. X-ray diffraction space group of single crystals of P21 / n, c. Parameters: a=11.83974(13)Å, b=23.5195(2)Å, c=14.48807(17)Å, α=90°, β=101.5333(11)°, γ=90°, V=3952.96(7)Å 3 X-ray diffraction unit cell of a single crystal having d. The differential scanning calorimetry (DSC) curves shown in Figure 12B, and e. Differential scanning calorimetry (DSC) curves exhibiting exothermic properties starting at approximately 201°C. It is characterized by three or more of the following.

[0154] In some embodiments, the solvated crystalline form of compound 1 is form E. In some embodiments, crystalline form E is a. The X-ray powder diffraction (XRPD) pattern is substantially shown in Figure 11. b. X-ray diffraction space group of single crystals of P21 / n, c. Parameters: a=11.83974(13)Å, b=23.5195(2)Å, c=14.48807(17)Å, α=90°, β=101.5333(11)°, γ=90°, V=3952.96(7)Å 3 X-ray diffraction unit cell of a single crystal having d. The differential scanning calorimetry (DSC) curves shown in Figure 12B, and e. Differential scanning calorimetry (DSC) curves exhibiting exothermic properties starting at approximately 201°C. It is characterized by four or more of the following.

[0155] In some embodiments, the solvated crystalline form of compound 1 is form E. In some embodiments, crystalline form E is a. The X-ray powder diffraction (XRPD) pattern is substantially shown in Figure 11. b. X-ray diffraction space group of single crystals of P21 / n, c. Parameters: a=11.83974(13)Å, b=23.5195(2)Å, c=14.48807(17)Å, α=90°, β=101.5333(11)°, γ=90°, V=3952.96(7)Å 3 X-ray diffraction unit cell of a single crystal having d. The differential scanning calorimetry (DSC) curves shown in Figure 12B, and e. Differential scanning calorimetry (DSC) curves exhibiting exothermic properties starting at approximately 201°C. It is characterized by:

[0156] In one or more embodiments, the crystalline form E of compound 1 is characterized by differential scanning calorimetry (DSC) having exothermic reactions between 195°C and 205°C. For example, form E of compound 1 may be characterized by differential scanning calorimetry (DSC) having exothermic reactions at 195°C, 196°C, 197°C, 198°C, 199°C, 200°C, 201°C, 202°C, 203°C, 204°C, or 205°C. For example, form E of compound 1 may be characterized by differential scanning calorimetry (DSC) having exothermic reactions at approximately 195°C, approximately 196°C, approximately 197°C, approximately 198°C, approximately 199°C, approximately 200°C, approximately 201°C, approximately 202°C, approximately 203°C, approximately 204°C, or approximately 205°C. In some embodiments, the crystalline form E of compound 1 is characterized by differential scanning calorimetry (DSC) which has an exothermic reaction of 190°C.

[0157] In some embodiments, the crystalline form of compound 1 is morphology F, and it exhibits an XRPD pattern including at least one peak selected from the group consisting of 9.9, 11.9, 17.3, 19.4, and 25.7 degrees 2θ ± 0.2 degrees 2θ.

[0158] In some embodiments, the crystalline form of compound 1 is morphology F, and it exhibits an XRPD pattern further including at least one additional peak selected from the group consisting of 9.7, 12.1, 20.8, 23.2, 23.7, 24.2, 25.0, and 26.4 degrees 2θ ± 0.2 degrees 2θ.

[0159] In some embodiments, the disclosure provides a crystalline form of compound 1, which is solvated. In some embodiments, the solvated crystalline form of compound 1 is a hydrate. In some embodiments, the solvated crystalline form of compound 1 is form F. In some embodiments, crystalline form F is a. The X-ray powder diffraction (XRPD) pattern is substantially shown in Figure 13. b. X-ray diffraction unit cell of triclinic single crystals, and c. Approximately 511Å3 The X-ray diffraction formula per unit volume of a single crystal, and d. Differential scanning calorimetry (DSC) curve with exothermic reaction of approximately 120°C. Characterized by one or more of these.

[0160] In some embodiments, the crystal morphology F is a. The X-ray powder diffraction (XRPD) pattern is substantially shown in Figure 13. b. X-ray diffraction unit cell of triclinic single crystals, and c. Approximately 511Å 3 The X-ray diffraction formula per unit volume of a single crystal, and d. Differential scanning calorimetry (DSC) curve with exothermic reaction of approximately 120°C. Characterized by two or more of these.

[0161] In some embodiments, the crystal morphology F is a. The X-ray powder diffraction (XRPD) pattern is substantially shown in Figure 13. b. X-ray diffraction unit cell of triclinic single crystals, and c. Approximately 511Å 3 The X-ray diffraction formula per unit volume of a single crystal, and d. Differential scanning calorimetry (DSC) curve with exothermic reaction of approximately 120°C. It is characterized by three or more of the following.

[0162] In some embodiments, the crystal morphology F is a. The X-ray powder diffraction (XRPD) pattern is substantially shown in Figure 13. b. X-ray diffraction unit cell of triclinic single crystals, and c. Approximately 511Å 3 The X-ray diffraction formula per unit volume of a single crystal, and d. Differential scanning calorimetry (DSC) curve with exothermic reaction of approximately 120°C. It is characterized by:

[0163] In one or more embodiments, the crystalline form F of compound 1 is 506 Å. 3 ~516Å3 is characterized by the X-ray diffraction unit volume of a single crystal of. For example, Form F of Compound 1 is 506 Å 3 , 507 Å 3 , 508 Å 3 , 509 Å 3 , 510 Å 3 , 511 Å 3 , 512 Å 3 , 513 Å 3 , 514 Å 3 , 515 Å 3 , 516 Å 3 may also be characterized by the X-ray diffraction unit volume of a single crystal of. In some embodiments, Crystal Form F of Compound 1 is 511 Å 3 is characterized by the X-ray diffraction unit volume of a single crystal of.

[0164] In one or more embodiments, Crystal Form F of Compound has a differential scanning calorimetry (DSC) with an exotherm at 115 °C to 130 °C. For example, Form F of Compound 1 may be characterized by differential scanning calorimetry (DSC) having an exotherm at 115 °C, 116 °C, 117 °C, 118 °C, 119 °C, 120 °C, 121 °C, 122 °C, 123 °C, 124 °C, 125 °C, 126 °C, 127 °C, 128 °C, 129 °C or 130 °C. For example, Form F of Compound 1 may be characterized by differential scanning calorimetry (DSC) having an exotherm at about 115 °C, about 116 °C, about 117 °C, about 118 °C, about 119 °C, about 120 °C, about 121 °C, about 122 °C, about 123 °C, about 124 °C, about 125 °C, about at 120 °C. In some embodiments, Crystal Form F of Compound 1 is characterized by differential scanning calorimetry (DSC) having an exotherm at about 120 °C. In some embodiments, Crystal Form F of Compound 1 is characterized by differential scanning calorimetry (DSC) having an exotherm above about 120 °C.

[0165] In one or more embodiments, the disclosure relates to a crystalline form of compound 1 characterized by higher thermodynamic stability compared to other crystalline forms of compound 1. The thermodynamic stability of crystalline forms A, B, C, E, and F was investigated, and it was determined that polymorph A of compound 1 has superior thermodynamic stability compared to form B, substance D, form C, form E, and form F. Polymorph A also has limited hygroscopicity, maintains crystallinity and potency, and facilitates handling. Therefore, in some embodiments, the disclosure relates to a crystalline form of compound 1, where the crystalline form corresponds to form A. Pharmaceutical compositions and combinations

[0166] In one embodiment, the Disclosure provides pharmaceutical compositions and combinations comprising a crystalline form of compound 1 (e.g., form A, form B, form C, form E, or form F) and optionally one or more further therapeutic agents. In some embodiments, the Disclosure provides pharmaceutical compositions and combinations comprising a crystalline form of compound 1 which is form A, and optionally one or more further therapeutic agents. In some embodiments, one or more further therapeutic agents are selected from the group consisting of antipsychotics, memantine, SV2A inhibitors, and AChEIs, or any pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or prodrugs. In some embodiments, at least one of the one or more further therapeutic agents is an SV2A inhibitor selected from the group consisting of levetiracetam, celetracetam, and brivalacetam, or any pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or prodrugs. In some embodiments, at least one of the one or more further therapeutic agents is an antipsychotic selected from the group consisting of aripiprazole, olanzapine, and ziprasidone, or any pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug of any of the foregoing. In some embodiments, at least one of the one or more further therapeutic agents is memantine, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its prodrug. In some embodiments, at least one of the one or more further therapeutic agents is an AChEI selected from the group consisting of donepezil, galantamine, amvenonium, and rivastigmine, or any pharmaceutically acceptable salt, hydrate, solvate, polymorph, or prodrug of any of the foregoing. In some embodiments, the pharmaceutical compositions and combinations described herein include a crystalline form of compound 1 and one or more further therapeutic agents. In some embodiments, the pharmaceutical compositions and combinations described herein include more than the crystalline form of compound 1.

[0167] In some embodiments, the Disclosure provides a pharmaceutical combination comprising a first pharmaceutical composition comprising a crystalline form of compound 1 as described herein (e.g., form A, form B, form C, form E, or form F), and one or more further pharmaceutical compositions comprising a therapeutic agent selected from the group consisting of antipsychotics, memantine, SV2A inhibitors, and AChEIs, or any of the aforementioned pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or prodrugs. In some embodiments, the Disclosure provides a pharmaceutical combination comprising a first pharmaceutical composition comprising a crystalline form of compound 1 which is form A as described herein, and one or more further pharmaceutical compositions comprising a therapeutic agent selected from the group consisting of antipsychotics, memantine, SV2A inhibitors, and AChEIs, or any of the aforementioned pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or prodrugs. In some embodiments, the first pharmaceutical composition comprises one or more crystalline forms of compound 1. In some embodiments, at least one of one or more further pharmaceutical compositions comprises an SV2A inhibitor selected from the group consisting of levetiracetam, celetracetam, and brivalacetam, or any pharmaceutically acceptable salt, hydrate, solvate, polyform, or prodrug. In some embodiments, at least one of one or more further pharmaceutical compositions comprises an antipsychotic agent selected from the group consisting of aripiprazole, olanzapine, and ziprasidone, or any pharmaceutically acceptable salt, hydrate, solvate, polyform, or prodrug. In some embodiments, at least one of one or more further pharmaceutical compositions comprises memantine, or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polyform, or its prodrug. In some embodiments, at least one of one or more further pharmaceutical compositions comprises an AChEI selected from the group consisting of donepezil, galantamine, amvenonium, and rivastigmine, or any pharmaceutically acceptable salt, hydrate, solvate, polyform, or prodrug of any of the foregoing.

[0168] In some embodiments, the first and one or more further pharmaceutical compositions are formulated separately. In certain such embodiments, the first and one or more further pharmaceutical compositions are packaged together. In some embodiments, the first and one or more further pharmaceutical compositions are packaged separately. In some embodiments, the first and one or more further pharmaceutical compositions are formulated together.

[0169] In certain embodiments, one or more of the pharmaceutical compositions and combinations or their components according to this disclosure are formulated in solid form. In certain embodiments, one or more of the pharmaceutical compositions and combinations or their components according to this disclosure are formulated in liquid form. In certain embodiments, one or more of the pharmaceutical compositions and combinations or their components according to this disclosure are formulated in suspension form. In certain embodiments, one or more of the pharmaceutical compositions and combinations or their components according to this disclosure are formulated in unit dosage forms. In certain embodiments, one or more of the pharmaceutical compositions and combinations or their components according to this disclosure are formulated in capsule or tablet form. In certain embodiments, one or more of the pharmaceutical compositions and combinations or their components according to this disclosure are formulated for oral administration. In certain embodiments, one or more of the pharmaceutical compositions and combinations or their components according to this disclosure are formulated for intra-parenteral administration.

[0170] In some embodiments, the pharmaceutical compositions and combinations described herein, or one or more of their components, are formulated with a pharmaceutically acceptable carrier. Examples of pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts, or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulosic substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene polyoxypropylene block polymers, polyethylene glycol, and lanolin. Suitable aqueous and non-aqueous carriers that may be used in the pharmaceutical compositions or combinations (or their components) of this disclosure include water, ethanol, polyols (e.g., glycerol, propylene glycol, polyethylene glycol, etc.), and suitable mixtures thereof, vegetable oils (e.g., olive oil), and organic esters for injection (e.g., ethyl oleate). Appropriate fluidity can be maintained, for example, by the use of coating materials such as lecithin, by maintaining the required particle size in the case of dispersions, and by the use of surfactants. In some embodiments, no carrier is used. The pharmaceutical compositions and combinations described herein can be formulated in any convenient manner for use in human medicine.

[0171] The pharmaceutical compositions and combinations described herein, or one or more of their components, can be formulated for administration by any suitable route, as described herein and as known in the art. For example, the pharmaceutical compositions and combinations (or one or more of their components) described herein for parenteral administration (e.g., subcutaneous, intravenous, intraarterial, intradermal, intramuscular, intraperitoneal) or intrathecal or intracerebral administration include sterile aqueous and non-aqueous injection solutions, dispersions, suspensions or emulsions, and sterile powders that are reconstituted into sterile injection solutions or dispersions prior to use, which may contain antioxidants, buffers, bacteriostatic agents, solutes that render the pharmaceutical composition or combination (or its components) isotonic with the blood of the intended recipient, or suspending or thickening agents. When administered parenterally, the crystalline forms of Compound 1 described herein, and / or one or more additional therapeutic agents, may be in pyrogen-free and physiologically acceptable forms. Techniques and formulations can generally be found in Remington's Pharmaceutical Sciences, Meade Publishing Co., Easton, PA.

[0172] The pharmaceutical compositions or combinations according to the disclosure for buccal and oral delivery (sublingual and buccal administration, e.g., Danckwerts et al., and including oral) include, but are not limited to, bioadhesive polymers, tablets, patches, films, solutions and semi-solids (see, e.g., Smart et al.).

[0173] In some embodiments, the pharmaceutical compositions or combinations (or one or more of their components) according to this disclosure may be in solid dosage forms such as capsules, tablets, sugar-coated tablets, pills, lozenges, cachets, powders, troches, wafers, or granules. In solid dosage forms for oral administration, the crystalline form of compound 1 described herein, and / or one or more further therapeutic agents may be mixed with one or more pharmaceutically acceptable carriers, such as sodium citrate or dicalcium phosphate, and / or any of the following: (1) fillers or bulking agents, e.g., starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) binders, e.g., carboxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose and / or acacia; (3) humectants, e.g. (1) For example, glycerol, (4) disintegrants, such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, (5) dissolution retarders, such as paraffin, (6) absorption enhancers, such as quaternary ammonium compounds, (7) wetting agents, such as cetyl alcohol and glycerol monostearate, (8) absorbents, such as kaolin and bentonite clay, (9) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate and mixtures thereof, and (10) colorants. In the case of capsules, tablets and pills, the pharmaceutical compositions or combinations (or components thereof) of the present disclosure may also include buffers. Similar types of solid pharmaceutical compositions or combinations (or components thereof) may also be used as fillers in soft and hard gelatin capsules with the use of excipients such as lactose and high molecular weight polyethylene glycol.

[0174] In some embodiments, the pharmaceutical composition or combination (or one or more of its components) according to the present disclosure may also be in an aqueous or non-aqueous liquid dosage form including a solution, emulsion, microemulsion, suspension, syrup, troche, or elixir. In some embodiments, the pharmaceutical composition or combination of the present disclosure is in an aqueous solution. In some embodiments, the pharmaceutical composition or combination of the present disclosure is in a suspension form. Where appropriate, the pharmaceutical composition or combination of the present disclosure can be prepared using a coating such as an enteric coating, or formulated according to methods well known in the art to provide sustained release (e.g., controlled release, long-term release, sustained release, delayed release, or slow release) of crystalline forms of Compound 1, and / or one or more additional therapeutic agents. The liquid dosage form may also include inert diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents, such as ethyl alcohol (ethanol), isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to the inert diluent, the oral pharmaceutical composition or combination can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents, coloring agents, perfumes and preservatives. In some embodiments, the pharmaceutical composition or combination (or one or more of their components) according to the present disclosure can include suspending agents such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol, and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar and tragacanth, and mixtures thereof.

[0175] Pharmaceutical compositions or combinations of the present disclosure for respiratory delivery (lung and nasal delivery), or one or more of their components, include, but are not limited to, a variety of pressurized metered-dose inhalers, dry powder inhalers, nebulizers, aqueous mist inhalers, drops, solutions, suspensions, sprays, powders, gels, ointments, and special systems such as liposomes and microspheres (see, for example, Owens et al., "Alternative Routes of Insulin Delivery" and Martini et al.). Pharmaceutical compositions or combinations of the present disclosure (or their components) for transdermal delivery include, but are not limited to, colloids, patches, and microemulsions.

[0176] Other suitable dosage forms for the pharmaceutical compositions or combinations of the present disclosure (or one or more of their components) include depot injection formulations, suppositories, sprays, ointments, creams, gels, inhalants, skin patches, implants, devices, formulations for ocular administration, and the like.

[0177] The pharmaceutical compositions or combinations of the present disclosure, or one or more of their components, may also contain adjuvants such as preservatives, humectants, emulsifiers, and dispersants. Prevention of microbial action may be ensured by including various antibacterial and antifungal agents, such as parabens, chlorobutanol, and phenol sorbic acid. It may also be desirable to include isotonic agents such as sugars and sodium chloride in the pharmaceutical compositions or combinations or components. Furthermore, long-term absorption of the injectable pharmaceutical form may be achieved by including absorption-delaying agents such as aluminum monostearate and gelatin.

[0178] The pharmaceutical compositions or combinations described herein can be prepared by methods well known in the pharmaceutical art, see, for example, Goodman et al., 2001; Ansel, et al., 2004; Stoklosa et al., 2001; and Bustamante, et al., 1993.

[0179] In some embodiments, the pharmaceutical compositions and / or combinations according to this disclosure contain crystalline forms of Compound 1 (e.g., Form A, Form B, Form C, Form E, or Form F) in amounts ranging from 0.05 mg to 5000 mg or from 5 mg to 1000 mg. In some embodiments, the pharmaceutical composition may contain crystalline forms of Compound 1 in amounts ranging from about 0.5 mg, about 5 mg, about 20 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg, about 250 mg, about 500 mg, about 750 mg, about 1000 mg, about 1250 mg, about 2500 mg, about 3500 mg, or 5000 mg.

[0180] In some embodiments of pharmaceutical compositions and / or combinations comprising an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, the SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer is present in amounts of 0.07 mg to 60 mg, 0.07 mg to 350 mg, 3 mg to 50 mg, 3 mg to 60 mg, 25 mg to 60 mg, 25 mg to 125 mg, 50 mg to 250 mg, 5 mg to 140 mg, 0.7 mg to 180 mg, 125 mg to 240 mg, or 190 to 220 mg. In some embodiments of pharmaceutical compositions and / or combinations comprising an SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer, the SV2A inhibitor (e.g., levetiracetam, brivalacetam, or celetracetam), or a pharmaceutically acceptable salt thereof, its hydrate, its solvate, its polymorph, or its isomer is present in an amount of 220 mg. Method for generating the crystalline form of compound 1

[0181] The exemplary methods described herein are useful for producing crystalline forms of compound 1. In some embodiments, the disclosure relates to a method for producing crystalline forms of compound 1, where the crystalline form is form A, form B, form C, form E, or form F. In some embodiments, the method according to the disclosure relates to the production of crystalline form A of compound 1.

[0182] In some embodiments, the method disclosed herein is a method for producing form A, which is an anhydrous crystalline form of compound 1, a. A step of dissolving the compound in a first solvent at a first temperature to produce a solution. b. Adding a second solvent to the solution to form a mixture, c. If necessary, the step of cooling the mixture to a second temperature, and d. The obtained precipitate is collected to obtain form A, which is the anhydrous crystalline form of the compound. This includes methods.

[0183] In some embodiments of this disclosure, the first and second solvents are selected from the group consisting of acetone, acetonitrile, tetrahydrofuran, dichloromethane, dimethylformamide, ethanol, methanol, ethyl acetate, diethyl ether, toluene, water, or any mixture thereof.

[0184] In some embodiments, the first solvent is dichloromethane, dimethylformamide, tetrahydrofuran, or any mixture thereof. In some embodiments, the first solvent is dimethylformamide.

[0185] The first solvent can be added to compound 1 using several methods recognized by those skilled in the art. For example, the solvent can be added to compound 1 by pouring it into a container containing compound 1, by pipetting, or by transferring it with a cannula. Alternatively, compound 1 can be added to a container containing the solvent. In some embodiments, the solution containing the first solvent and compound 1 is stirred, for example, by agitation, to aid in the dissolution of compound 1. In some embodiments, the solution containing the solvent and compound 1 is adjusted to a first temperature to aid in the dissolution of compound 1. In some embodiments, the first temperature is the ambient temperature, for example, about 20°C to about 22°C. In some embodiments, the first temperature is at least 20°C. In some embodiments, the solution containing the first solvent and compound 1 is dilute, concentrated, nearly saturated, or saturated. In some embodiments, the solution containing the first solvent and compound 1 is nearly saturated or saturated.

[0186] In some embodiments, the second solvent in the method according to this disclosure is a poor solvent (i.e., a solvent in which compound 1 is partially soluble or insoluble) and is selected to induce a precipitate of compound 1 in a crystalline form (e.g., crystalline form A) from the solution. Those skilled in the art can determine which solvent compound 1 is soluble in through conventional experiments in the art. In some embodiments, the second solvent is ethanol, methanol, ethyl acetate, diethyl ether, toluene, or water. In some embodiments, the second solvent is water. The second solvent can be added to the mixture using techniques known to those skilled in the art. For example, the second solvent can be added to the solution by pouring the second solvent into the solution, pipetting, or transferring it with a cannula to form the mixture.

[0187] In some embodiments, the method optionally further includes the step of adjusting the first temperature to a second temperature different from the first temperature in order to induce precipitation of compound 1 in a crystalline form (e.g., crystalline form A). In some embodiments, the second temperature is less than the first temperature. In some embodiments, the second temperature is the ambient temperature (i.e., about 20°C to 22°C). In some embodiments, the second temperature is less than about 20°C. In some embodiments, the temperature is about -30°C to about 20°C. In some embodiments, the second temperature is 0°C to 20°C, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19°C. In some embodiments, the second temperature is about 0°C to about 20°C, for example, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, or about 19°C. In some embodiments, the mixture is not adjusted to the second temperature. As those skilled in the art will recognize, the length of time the mixture is maintained at the second temperature may vary based on the concentration of the solution and the temperature at which the solution is held. In some embodiments, the mixture is maintained at the second temperature for 1 hour to 7 days. In some embodiments, the mixture is maintained at the second temperature for at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days. In some embodiments, the mixture is maintained at the second temperature for at least 1 day, 2 days, or 3 days. In some embodiments, the mixture is maintained at a second temperature for about 1 hour to about 7 days.

[0188] The method according to this disclosure further includes the step of recovering the obtained precipitate from the mixture. The precipitate can be recovered using methods known to those skilled in the art, for example, by filtering the precipitate, decanting the mother liquor into another container to leave the precipitate, or by removing the mother liquor with a pipette.

[0189] In another embodiment, the present disclosure is a method for producing a crystalline form (e.g., form A) of compound 1, a. A step of dissolving the compound in a solvent to form a solution. b. A step of evaporating the solvent to produce a precipitate, and c. Step of collecting the precipitate to obtain the crystalline form of compound 1 (e.g., anhydrous crystalline form A). This provides a method that includes [something].

[0190] In some embodiments, the solvent is selected from the group consisting of acetone, acetonitrile, tetrahydrofuran, dichloromethane, dimethylformamide, ethanol, methanol, ethyl acetate, diethyl ether, toluene, water, or any mixture thereof. In some embodiments, the solvent is dichloromethane, dimethylformamide, tetrahydrofuran, or any mixture thereof.

[0191] The solvent can be evaporated from the solution using several methods known to those skilled in the art, such as evaporation under a stream of an inert gas, e.g., nitrogen; flash evaporation (i.e., evaporation under reduced pressure); evaporation by heating; or a combination thereof. In some embodiments, the solvent is evaporated under a stream of an inert gas, e.g., nitrogen. In some embodiments, the solvent is evaporated under reduced pressure. In some embodiments, the solvent is evaporated while heating the solution under reduced pressure. The temperature to which the solution is heated may depend on the boiling point of the solvent. In some embodiments, the solution is heated to at least the boiling point of the solvent. In some embodiments, the solvent is heated below the boiling point of the solvent. In some embodiments, the solution is heated to about 30°C to about 170°C. In some embodiments, the solution is heated to about 50°C to about 150°C, or about 70°C to about 120°C, or about 80°C to about 110°C. In some embodiments, the solution is heated to at least 80°C. The extent to which the solvent is evaporated may vary. In some embodiments, the solvent is evaporated until it is dry (i.e., so that at most a trace amount of solvent remains). In some embodiments, the solvent is evaporated until a precipitate forms.

[0192] The method further includes the step of recovering the precipitate to obtain the crystalline form of Compound 1 (i.e., anhydrous crystalline form A). The precipitate can be collected using methods known to those skilled in the art, for example, collected with a spatula, the residual solvent filtered, the residual solvent decanted, or the residual solvent removed from the precipitate with a pipette and then collected.

[0193] In another embodiment, the present disclosure provides a method for generating Form C, which is the methanolate crystalline form of Compound 1, comprising: a. combining the compounds in methanol to form a mixture; b. mixing the mixture for a predetermined period of time; c. optionally evaporating the methanol from the mixture; and d. recovering the precipitate to obtain Form C, which is the methanolate crystalline form of the compound. The method is provided.

[0194] Methanol can be added to Compound 1 using several methods recognized by those skilled in the art. For example, the solvent can be added to Compound 1 by pouring, pipetting, or transferring with a cannula of methanol into the container containing Compound 1. As another example, Compound 1 can be added to a container that already contains methanol. In some embodiments, methanol and Compound 1 are combined to form a slurry.

[0195] The mixture can be mixed for a period ranging from 30 minutes to 1 day. In some embodiments, the mixture is mixed for 30 minutes or 1 day.

[0196] In some embodiments, methanol is evaporated after the mixture has been mixed for a predetermined time. Methanol can be evaporated using several methods known to those skilled in the art. For example, the mixture can be dried by removing the solvent under reduced pressure or under an inert gas, such as a nitrogen stream. Alternatively, the mixture can be dried under reduced pressure and increased temperature. In some embodiments, the mixture is dried under reduced pressure at a temperature of at least 40°C. In certain such embodiments, the temperature is about 40°C to about 70°C. In some embodiments, the mixture is not dried. In some embodiments, the solvent is evaporated to dryness (i.e., so that at most trace amounts of methanol remain). In other embodiments, the solvent is removed to concentrate the mixture, i.e., to induce precipitation by forming a saturated solution.

[0197] The precipitate may be recovered using any method known to those skilled in the art. For example, the precipitate may be recovered by filtering the solution to isolate it. Alternatively, the precipitate may be recovered by decanting the mother liquor or by removing the mother liquor with a pipette.

[0198] In another embodiment, the present disclosure is a method for producing form B, which is a desolvated crystalline form of compound 1, a. Steps to obtain the methylate form C of the compound, b. Heat the compound for a predetermined time to form form B, which is the desolvated crystalline form of the compound. This provides a method that includes [something].

[0199] The methanolate form C of compound 1 can be obtained using the method described herein.

[0200] The method includes the step of heating the methanelate form C to expel the solvent and produce the desolvated form B. In some embodiments, the methanelate form C is heated above ambient temperature. In some embodiments, the methanelate form C is heated to at least 60°C. In some embodiments, the methanelate form C is heated to about 60°C to about 150°C. In some embodiments, the methanelate form C is heated to about 60°C to about 100°C. In some embodiments, the methanelate form C is heated to at least 80°C.

[0201] In some embodiments, the methanelate form C is heated for at least 1 hour, 2 hours, 4 hours, 3 hours, 4 hours, 5 hours, or 6 hours. In some embodiments, the methanelate form C is heated for 1 to 24 hours, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 hours. In some embodiments, the methanelate form C is heated for about 1 to about 24 hours, for example, about 1, about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, or about 24 hours.

[0202] In another embodiment, the present disclosure is a method for producing form F, which is a monohydrate crystalline form of compound 1, a. Steps to obtain the hydrochloride salt of the compound, b. Adding the hydrochloride salt of the compound to the solvent to form a mixture. c. A step of mixing the mixture for a predetermined time, d. The step of collecting the precipitate to obtain form F, which is the monohydrate crystalline form of the compound. This provides a method that includes [something].

[0203] In some embodiments, the hydrochloride salt of compound 1 is obtained by reacting compound 1 with hydrochloric acid. Compound 1 can be reacted with hydrochloric acid by dissolving compound 1 in a solvent and adding a stoichiometric amount or an excess of HCl to the mixture. The solvent can be selected from the group consisting of acetone, acetonitrile, tetrahydrofuran, dichloromethane, dimethylformamide, ethanol, methanol, ethyl acetate, diethyl ether, toluene, water, or any mixture thereof. In some embodiments, the hydrochloride salt is isolated before being used to produce form F, which is a monohydrate crystalline form. The hydrochloride salt can be isolated by methods known to those skilled in the art, such as filtration, drying under reduced pressure, and recrystallization.

[0204] The solvent to which the hydrochloride salt is added in step (b) of the method can be selected from the group consisting of acetone, acetonitrile, tetrahydrofuran, dichloromethane, dimethylformamide, ethanol, methanol, ethyl acetate, diethyl ether, toluene, water, or any mixture thereof. In some embodiments, the solvent is water. The mixture is then mixed (i.e., stirred or agitated) over a period ranging from 1 to 14 days. In some embodiments, the mixture is mixed for at least 1 day. In other embodiments, the mixture is mixed for at least 6 days.

[0205] Next, the precipitate may be recovered using any method known to those skilled in the art. For example, the precipitate may be recovered by filtering the solution to isolate the precipitate. Alternatively, the precipitate may be recovered by decanting the mother liquor or by removing the mother liquor with a pipette.

[0206] In another embodiment, the present disclosure provides a method for producing form E, which is an anhydrous crystalline form of compound 1, a. Dissolve the compound in tetrahydrofuran at a first temperature to form a solution. b. A step of adjusting the first temperature to the second temperature to induce precipitation, c. The precipitate is collected to obtain form E, which is the anhydrous crystalline form of the compound. This provides a method that includes [something].

[0207] In some embodiments, the first temperature is the ambient temperature, for example, about 20°C to 22°C. In some embodiments, the first temperature is at least 20°C. In some embodiments, the first temperature is about 20°C to about 66°C. In some embodiments, the solution containing the first solvent and compound 1 is dilute, concentrated, nearly saturated, or saturated. In some embodiments, the solution containing the first solvent and compound 1 is nearly saturated or saturated.

[0208] In some embodiments, the method optionally further includes the step of adjusting the first temperature to a second temperature different from the first temperature in order to induce precipitation of compound 1 in a crystalline form (e.g., anhydrous crystalline form E). In some embodiments, the second temperature is less than the first temperature. In some embodiments, the second temperature is less than 66°C. In some embodiments, the second temperature is less than 20°C. In some embodiments, the temperature is about -30°C to about 30°C. In some embodiments, the second temperature is 0°C to 20°C, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18 or 19°C. In some embodiments, the second temperature is approximately 0°C to approximately 20°C, for example, approximately 1, approximately 2, approximately 3, approximately 4, approximately 5, approximately 6, approximately 7, approximately 8, approximately 9, approximately 10, approximately 11, approximately 12, approximately 13, approximately 14, approximately 15, approximately 16, approximately 17, approximately 18, or approximately 19°C. As those skilled in the art will recognize, the length of time the mixture is maintained at the second temperature may vary based on the concentration of the solution and the temperature at which the solution is held. In some embodiments, the mixture is maintained at the second temperature for 1 hour to 7 days. In some embodiments, the mixture is maintained at the second temperature for at least 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days. In some embodiments, the mixture is maintained at the second temperature for at least 1 day, 2 days, or 3 days. In some embodiments, the mixture is maintained at a second temperature for about 1 hour to about 7 days.

[0209] It will be understood by those skilled in the art that the methods described herein may be adapted and modified to suit the intended use, that the methods described herein may be used in other suitable uses, and that such other additions and modifications will not depart from the scope of the invention.

[0210] This disclosure will be better understood from the details of the subsequent examples and experiments. However, those skilled in the art will readily recognize that the specific methods and results discussed are merely illustrative of the invention, which will be described more fully in subsequent embodiments. [Examples]

[0211] (Example 1) Synthesis of Compound 1 [ka] Preparation of 2-((2,4-dimethoxybenzyl)amino)acetic acid (C). [ka]

[0212] A mixture of compound A (40.0 g, 240 mmol), compound B (50.2 g, 360 mmol), and Et3N (50.2 mL, 360 mmol) in anhydrous CH2Cl2 (800 mL) was stirred at room temperature under N2 for 1 hour. After this time, NaBH(OAc)3 (76.4 g, 360 mmol) was added in small amounts over 20 minutes in a cold water cooling bath (exothermic). The resulting mixture was stirred at room temperature overnight. Next, the reaction mixture was cooled in an ice / water bath and quenched by slowly adding saturated NaHCO3 aqueous solution (approximately 800 mL). The resulting mixture was stirred for 30 minutes. The layers were separated. The aqueous layer was extracted with CH2Cl2 (2 × 500 mL). The combined organic layers were washed with saturated NaHCO3 aqueous solution (300 mL) and water (300 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in methanol (320 mL). A 2N aqueous solution of NaOH (360 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. After this time, the reaction mixture was cooled in an ice / water bath, and concentrated HCl (approximately 12N) was slowly added to acidify it to pH 4-5. The resulting mixture was concentrated under reduced pressure. Water (80 mL) was added to the residue, and the mixture was stirred in a 70°C bath until all solids were dissolved. The resulting solution was cooled in an ice / water bath and sonicated for 10 minutes. The solid was collected by filtration and dried under high vacuum to obtain compound C as a white solid (44.3 g, 82%). 1 H NMR (500 MHz, DMSO-d6) δ 7.26 (d, J = 8.3 Hz, 1H), 6.59 (d, J = 2.4 Hz, 1H), 6.53 (dd, J = 8.3, 2.4 Hz, 1H), 3.92 (s, 2H), 3.80 (s, 3H), 3.77 (s, 3H), 3.04 (s, 2H). Preparation of 7-chloro-4-(2,4-dimethoxybenzyl)-3,4-dihydro-1H-benzo[e][1,4]diazepine-2,5-dione(E). [ka]

[0213] A suspension of compound C (12.5 g, 55.5 mmol) and compound D (10.0 g, 50.6 mmol) in xylene (140 mL) was heated under N2 with stirring for 3 hours under reflux. After this time, the reaction mixture was cooled to room temperature and concentrated to dryness under reduced pressure. The residue was triturated with  / methanol (10:1, approximately 40 mL) and filtered. The filtered cake was dried under high vacuum to obtain compound E as an off-white solid (14.0 g, 77%). ESI MS, m / z=361[M+H] + . Preparation of ethyl 8-chloro-5-(2,4-dimethoxybenzyl)-6-oxo-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate (F). [ka]

[0214] Compound E (23.0 g, 63.7 mmol) was stirred in anhydrous THF (250 mL) and anhydrous DMF (125 mL) to which NaH (60% in mineral oil, 3.82 g, 95.5 mmol) was added under N2 conditions at -20°C. The resulting mixture was warmed to room temperature and stirred at room temperature for 30 minutes. After this time, the reaction mixture was cooled to -20°C and (EtO)2P(O)Cl (13.8 mL, 95.5 mmol) was added. Next, the resulting mixture was warmed to room temperature and stirred at room temperature for 2.5 hours. The reaction mixture was cooled in an ice / water bath and CNCH2CO2Et (10.4 mL, 95.2 mmol) was added. The resulting mixture was stirred at 0°C for 5 minutes and then cooled to -78°C. NaH (60% in mineral oil, 3.82 g, 95.5 mmol) was added. The reaction mixture was stirred at -78°C for 10 minutes and slowly warmed to room temperature overnight. After this time, the reaction mixture was quenched with a semi-saturated aqueous solution of NaHCO3 (400 mL) and extracted with  (3 × 400 mL). The combined extract was washed with a 10% aqueous solution of LiCl (2 × 100 mL) and brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluted with 80%–100%  / CH2Cl2 to obtain compound F as an off-white solid (18.3 g, 63%): ESI MS, m / z = 456 [M + H]. + . Preparation of ethyl 8-chloro-6-oxo-5,6-dihydro-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate (G). [ka]

[0215] To a stirred solution of compound F (18.3 g, 40.1 mmol) in anhydrous CH2Cl2 (96 mL), TFA (48 mL) was added at 0°C, followed by TfOH (7.1 mL, 80.8 mmol). The reaction mixture was warmed to room temperature and stirred for 2 hours. After this time, the reaction mixture was concentrated under reduced pressure. The residue was diluted with CH2Cl2 (300 mL), cooled in an ice / water bath, and basicized to pH > 7 by slowly adding saturated NaHCO3 aqueous solution. The mixture was filtered. The filtrate cake was washed with water (2 × 30 mL). The filtrate layers were separated. The aqueous layer was extracted with CH2Cl2 (4 × 300 mL). The combined organic layers were washed with water (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was tritulated with siRNA and filtered. The combined filtrate cake was dried under high vacuum to obtain compound G as an off-white solid (12.9 g, >99%). ESI MS, m / z=306[M+H] + . Preparation of ethyl 3-chloro-7-(methoxymethyl)-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine-10-carboxylate (I). [ka]

[0216] To a stirred suspension of compound G (12.9 g, approximately 40.1 mmol) and compound H (23.1 mL, 160 mmol) in chlorobenzene (400 mL), POCl3 (7.5 mL, 80.5 mmol) was added at room temperature under N2. The reaction mixture was heated in an oil bath (reflux) at 150 °C with stirring for 2.5 hours. After this time, the reaction mixture was cooled to room temperature, and CH3OCH2C(O)NHNH2 (25.0 g, 240 mmol) was added, followed by DIPEA (35 mL, 201 mmol). The resulting mixture was stirred at room temperature for 30 minutes, then heated in an oil bath at 135 °C for 1.5 hours. After this time, the reaction mixture was cooled to room temperature, diluted with CH2Cl2 (500 mL), and quenched with saturated NaHCO3 aqueous solution (500 mL). The layers were separated. The aqueous layer was extracted with CH2Cl2 (4 × 300 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluted with 0%-8% MeOH / siRNA to obtain compound I as a pale yellow solid (11.5 g, 77%). ESI MS, m / z=374[M+H] + Compound G (1.80g) was also recovered. Preparation of (3-chloro-7-(methoxymethyl)-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine-10-yl)methanol (J). [ka]

[0217] To a stirred solution of Compound I (3.74 g, 10.0 mmol) in anhydrous THF (40 mL), DIBAL-H (1 M in THF, 30 mL, 30 mmol) was added dropwise at 0 °C under N₂ over 10 minutes. The reaction mixture was stirred at 0 °C for 2.5 hours. After this time, the reaction mixture was quenched with saturated Rochelle salt aqueous solution (40 mL) and water (50 mL). The resulting mixture was stirred at room temperature for 1.5 hours. The solid was filtered off and washed with water (10 mL) and EtOAc (10 mL). The layers of the filtrate were separated. The aqueous layer was extracted with EtOAc (3 × 30 mL). The combined organic layers were dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was triturated with EtOAc (5 mL) and filtered. The combined filter cakes were dried under high vacuum to give Compound G as a pale yellow solid (2.95 g, 89%). ESI MS, m / z = 354 [M + Na] + . Preparation of 3-chloro-7-(methoxymethyl)-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine-10-carbaldehyde (K). [Chemical formula]

[0218] To a stirred suspension of Compound J (2.95 g, 8.89 mmol) in anhydrous CH₂Cl₂ (50 mL), Dess-Martin periodinane (4.53 g, 10.7 mmol) was added at 0 °C under N₂. The resulting mixture was stirred at 0 °C for 10 minutes and then warmed to room temperature over 3 hours. After this time, the reaction mixture was quenched with methanol (5 mL) and stirred at room temperature for 1 hour. Brine (50 mL) was added to the resulting mixture. The layers were separated. The aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluting with EtOAc, then 0% - 10% MeOH / CH₂Cl₂ to give Compound K as a white solid (2.62 g, 89%). ESI MS, m / z = 330 [M + H] + . Preparation of 3-chloro-10-ethynyl-7-(methoxymethyl)-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine(L). [ka]

[0219] To a stirred solution of compound K (2.62 g, 7.95 mmol) in anhydrous MeOH (70 mL), K2CO3 (2.20 g, 15.9 mmol), followed by Bestmann-Ohira reagent (2.29 g, 11.9 mmol), was added at room temperature under N2. The reaction mixture was stirred overnight at room temperature. After this time, the reaction mixture was quenched with saturated NaHCO3 aqueous solution. The resulting mixture was extracted with CH2Cl2 (3 × 50 mL). The combined extract was concentrated under reduced pressure. The residue was dissolved in CH2Cl2 (200 mL), washed with water (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was tritulated with CH2Cl2 (10 mL) and filtered. The filtrate was purified by flash column chromatography on silica gel eluted with 2%-4% MeOH / siRNA. The product obtained from column purification was combined with the filtration cake and dried under high vacuum to obtain compound L as a white solid (1.96 g, 76%): ESI MS, m / z = 326 [M + H]. + . Preparation of 5-((3-chloro-7-(methoxymethyl)-9H-benzo[f]imidazo[1,5-a][1,2,4]triazolo[4,3-d][1,4]diazepine-10-yl)ethinyl)-2-methoxythiazole (1). [ka]

[0220] A suspension of compound L (500 mg, 1.53 mmol), compound M (see synthesis below) (1.10 g, 4.60 mmol), and CuI (87 mg, 0.460 mmol) in anhydrous DMF (15 mL) was bubbling with argon for 5 minutes. After this time, Et3N (1.07 mL, 7.65 mmol), followed by Pd(PPh3)4 (353 mg, 0.306 mmol) was added. The resulting mixture was stirred overnight at room temperature under argon. Next, the reaction mixture was diluted with water (50 mL) and extracted with pharmaceutically acceptable phosphate (4 × 50 mL). The combined extracts were washed with 10% LiCl aqueous solution (2 × 20 mL) and brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting residue was purified by flash column chromatography on silica gel eluted with 0%-5% MeOH / CH2Cl2 to obtain compound 1 as a pale gray solid (468 mg, 69%). 1 H NMR (300 MHz, DMSO-d6) δ 8.36 (s, 1H), 8.08 (d, J = 2.3 Hz, 1H), 7.97 (d, J = 8.7 Hz, 1H), 7.87 (dd, J = 8.7, 2.3 Hz, 1H), 7.62 (s, 1H), 5.43 (s, 2H), 4.76 (s, 2H), 4.09 (s, 3H), 3.31 (s, 3H);ESI MS, m / z=439[M+H] + . General Procedures for Salt and Polymorph Screening Addition of poor solvent

[0221] The solution was brought into contact with a poor solvent. These poor solvents were added to reduce the solubility of the solvent system and help induce crystallization. Cooling and slow cooling

[0222] Solutions were prepared in the selected solvent or solvent / poor solvent system. These solutions were cooled below room temperature in a refrigerator for varying time lengths to induce nucleation. Attention was paid to the presence or absence of solids. If solids were observed, the substance was isolated in an amount sufficient for analysis. If only an insufficient amount was present, further cooling was performed in a freezer. Samples were isolated either in a wet state for analysis or as a dry powder. Fast evaporation

[0223] The solution was prepared in the selected solvent and stirred while adding a fixed amount to aid elution. Once the mixture reached complete elution, as judged by visual observation, the solution was filtered through a 0.2 μm nylon filter and evaporated in an unstoppered vial at ambient temperature or under nitrogen at ambient temperature. The formed solid was isolated for evaluation. Slow evaporation

[0224] The solution was prepared in the selected solvent and stirred while adding a fixed amount to aid elution. When the mixture reached complete elution, as judged by visual observation, the solution was filtered through a 0.2 μm nylon filter and placed in a sample vial. The vial opening was covered with foil and perforated with 3x holes to allow slow evaporation at ambient temperature. The formed solid was isolated for evaluation. slurry

[0225] A solution was prepared by adding a sufficient amount of solid to the given solvent, ensuring that an excess of solid was present. This mixture was then stirred in a sealed vial at ambient temperature or high temperature. After a given time, the solid was isolated for analysis. Estimation of solubility

[0226] Based on visual observation, a fixed amount of various solvents was added to the given substance until complete elution was achieved, while stirring (usually by sonication) at a specified temperature. If elution occurred after the initial fixed amount was added, the value was reported as ">". If elution did not occur, the value was reported as "<". General instrumental techniques for salt and polymorph screening Differential Scanning Calorimetry (DSC)

[0227] DSC was performed using a Mettler-Toledo DSC3+ differential scanning calorimetry system. Tau lag adjustment was performed using indium, tin, and zinc. Temperature and enthalpy were adjusted using octane, phenyl salicylate, indium, tin, and zinc. This adjustment was then verified using octane, phenyl salicylate, indium, tin, and zinc. The sample was placed in an airtight aluminum DSC pan, its weight was accurately recorded, and the sample was inserted into the DSC cell. The weighed aluminum pan, configured as the sample pan, was placed on the reference side of the cell. Before sample analysis, a hole was made in the lid of the pan. The sample was analyzed at 10°C / min from -25°C to 250°C. Dynamic water vapor sorption (DVS)

[0228] Dynamic water vapor sorption data were collected using the DVS Intrinsic instrument of the Surface Measurement System. Samples were not dried before analysis. Solvation and desorption data were collected under nitrogen purging, in 10% RH increments, over a range of 5% to 95% RH. The equilibrium criteria used for analysis were a weight change of 0.001 dm / dt in 5 minutes, a minimum step time of 30 minutes, a maximum equilibrium time of 180 minutes, and a data logging interval of 3 minutes. Data were not corrected for the initial moisture content of the samples. Samples were identified as having low, limited, or high hygroscopicity based on the definitions in the table below. [Table 1A] Thermogravimetric analysis (TGA or TGA / DSC)

[0229] Thermogravimetric analysis was performed using a Mettler-Toledo TGA / DSC3+ analyzer. Temperature calibration was performed using calcium oxalate, indium, tin, and zinc. The sample was placed in an aluminum pan. This pan was airtight, a hole was made in the lid, and then the pan was placed in the TG furnace. The weighed aluminum pan configured as the sample pan was placed on the reference platform. The furnace was heated under nitrogen. The sample was analyzed at 10°C / min from 25°C to 350°C.

[0230] Thermogravimetric analysis typically involves an equilibrium period at the start of each analysis, usually indicated by red brackets in the thermogram. For accuracy in calculating the associated weight loss, the starting temperature is selected above this range (usually above 35°C).

[0231] DSC analysis with this instrument is not as sensitive as that of a DSC3+ differential scanning calorimetry. Therefore, samples containing sufficient solid matter are analyzed with both instruments, and only the TGA thermogram from this instrument is reported. X-ray powder diffraction (XRPD) Transmissive geometry (most samples)

[0232] XRPD patterns were collected using a PANalytical X'Pert PRO MPD or PANalytical Empyrean diffractometer, employing an incident beam of Cu irradiation generated using an Optix-length fine-focus source. A stepped elliptical multilayer mirror was used to penetrate the sample and focus the Cu KαX-rays onto the detector surface. Prior to analysis, a silicon sample (NIST SRM 640e) was analyzed to confirm that the observed position of the Si111 peak matched the NIST-certified position. The sample was sandwiched between 3 μm thick films and analyzed by transmission geometry. Background generated by air was minimized using beam stopping, a short antiscatter extension, and an antiscatter knife edge. Solar slits were used on the incident and diffracted beams to minimize broadening due to axial divergence. Diffraction patterns were collected using a scanning positional high-sensitivity detector (X'Celerator) located 240 mm from the sample and data acquisition software v.5.5. The data acquisition parameters for each pattern are displayed above the images in the data items of this report. All images, regardless of the equipment used, are labeled as X'Pert PRO MPD. (Example 2) Salt screening of compound 1

[0233] Unless otherwise specified, when referring to the use of Compound 1 in the following procedures, in some circumstances it refers to the mixture of Forms A and B observable after the synthesis of Compound 1 (see Figure 19), which is referred to herein as the “crude product.”

[0234] Compound 1 has a weak basic pK a Based on the value, strong acids were selected for salt formation. The eight strong acids used were hydrochloric acid, sulfuric acid, benzenesulfonic acid, ethane-1,2-disulfonic acid, methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, and toluenesulfonic acid.

[0235] These experiments generally involved directly adding 0.5, 1, or 2 molar equivalents of an acidic solution to a solution or suspension of compound 1 in its free base form. If a sufficient amount of precipitate formed, the substance was immediately harvested. Additional steps, including (but not limited to) cooling, addition of a poor solvent, melting / cooling, evaporation, and / or slurry formation, were performed in an attempt to increase the yield or crystallinity of the resulting substance.

[0236] The crystallinity of the products was qualitatively evaluated by polarized light microscopy (PLM) and / or X-ray powder diffraction (XRPD). Crystalline material was successfully isolated in all cases of the eight strong acids used. However, edisylates were... 1 Decomposition was confirmed by 1H NMR. With the exception of edisylate, at least one representative crystalline salt was isolated from each counterion. (Example 3) Polymorphic screening of free bases of compound 1

[0237] Unless otherwise specified, when referring to the use of Compound 1 in the following procedures, in some circumstances it refers to the mixture of Forms A and B observable after the synthesis of Compound 1 (see Figure 19), which is referred to herein as the “crude product.”

[0238] Table 1 summarizes the solvent-based screenings designed to identify the crystalline form of compound 1. Over 60 evaporation, slurry, grinding / precipitation, and cooling experiments were performed. In some cases, the solid was intentionally analyzed in a wet state to further increase the likelihood of identifying the hydrate or solvate form. Water-activated slurries were used to evaluate the tendency of compound 1 to form hydrates and to help identify the stable range in which hydrate formation occurs. Non-solvent-based methods consisting of heat-induced transformations were also included. Furthermore, experiments were conducted to help determine the relative thermodynamic stability between anhydrous forms at various temperatures (see Example 4). [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6]

[0239] Forms A, B, D, and E are the anhydrous forms of compound 1. Form F is the hydrate, and form C is the methanelate. The X-ray powder patterns of these forms are compared in Figures 1 and 2. The anhydrous crystalline form A of compound 1 exhibited limited hygroscopicity and decomposition initiation at 207°C, and was identified as the thermodynamically most stable compared to the other anhydrous forms of compound 1. Crystalline form B of compound 1 is a metastable desolvated form, obtained by desolvation of the methanelate of crystalline form C after overnight exposure at 80°C. Crystalline form E of compound 1 is a metastable anhydrous form, most frequently observed by disproportionation of various salts of compound 1 in water. Crystalline form F of compound 1 is a hydrate, produced in water by slurry formation of HCl salts of compound 1. The hydrate is derived from the crystalline structure of Cl - This is likely due to a displacement, which is unlikely to occur without the HCl salt as an intermediate. The hydrate was shown to remain unchanged for 5 days under vacuum at ambient temperature, but dehydration and decomposition occurred simultaneously upon exposure to 100°C. Characterization data will be discussed in more detail below. anhydrous form Form A, stable anhydrous substance

[0240] Crystal morphology A is the anhydrous form of compound 1, and decomposition begins at 207°C (Figures 3A and 3B). Morphology A is the most thermodynamically stable at ambient temperatures compared to the other anhydrous forms (see Example 4).

[0241] Form A can be produced from various solvents by slurrying in solvents with appropriate solubility, evaporation, cooling of saturated solutions, and addition of solvents / poor solvents (see Table 1). For example, when compound 1 was dissolved in dichloromethane (DCM) and then rapidly evaporated at either 80°C or under N2, form A of compound 1 was isolated. When seed crystals of form E of compound 1 were further added to the DCM solution and then rapidly evaporated under N2, pure form A of compound 1 was also isolated. Pure form A of compound 1 can also be isolated from various other experiments in dimethylformamide (DMF), tetrahydrofuran (THF), ethanol (EtOH), and mixtures of water and DMF.

[0242] The XRPD pattern and peak list for morphology A of compound 1 are illustrated in Figure 5 (experiment, top) and Table 2, respectively. [Table 2]

[0243] The single-crystal structure of morphology A was determined (Figure 4). A single crystal suitable for X-ray diffraction of morphology A was obtained by dissolving compound 1 in dimethylformamide, filtering this solution into ethanol, and cooling the mixture in a refrigerator (4°C) for 3 days to induce crystallization of morphology A. The crystal system is monoclinic, and the space group is C2 / c. The lattice parameters and calculated volume are: a=58.1415(14)Å, b=4.03974(8)Å, c=17.1204(3)Å, α=90°, β=90.261(2)°, γ=90°, V=4021.15(14)Å 3 The molecular weight is 438.89 gmol. -1 Therefore, Z=8, and the calculated density is 1.450 g / cm³. -3The results were as follows. Further details of the crystal data and crystallographic data acquisition parameters are summarized in Table 3. The asymmetric unit contains one molecule of compound 1. Thiazoles and ethers are rotated 180° and refined to an 88% occupancy in the dominant orientation. The atomic displacement elliptic diagram of morphology A of compound 1 in the primary orientation is shown in Figure 4. The calculated XRPD pattern from the single crystal data is compared with the experimental pattern in Figure 5. [Table 3-1] [Table 3-2]

[0244] Thermograms of form A are shown in Figures 3A and 3B. The TGA shows no weight loss up to a maximum of 207°C, consistent with the anhydrous form. The DSC curve shows exothermic reaction, with decomposition beginning at approximately 207°C.

[0245] Dynamic vapor sorption (DVS) isotherms suggest that morphology A exhibits low hygroscopicity (Figure 6). Hygroscopicity can be described as low, limited, or high, based in part on the concepts presented in the references (see dynamic vapor absorption experiments). The weight change due to the sorption / desorption cycle was negligible at approximately 0.3%, and there was no hysteresis. The material recovered from the DVS experiment was identified as identical to the starting material by XRPD. Metastable desolvated form of B

[0246] Form B is a metastable anhydride of compound 1, obtained by desolvation of polymorph C, which is the methanolate of compound 1, after exposure to 80°C overnight. Based on a thermogram of form C, the desolvated form (form B) shows decomposition initiation at approximately 190°C. Form B was shown to convert to form A at ambient temperature in solvent-mediated experiments (see Example 4), and it was confirmed that form B is metastable compared to form A under those conditions.

[0247] The XRPD pattern and its peak list for morphology B of compound 1 are illustrated in Figure 7 and Table 4, respectively. The XRPD pattern of morphology B is successfully indexed, providing a robust description of the crystalline morphology based on provisional crystallographic unit cell parameters, and strong evidence that the pattern is representative of the single-crystal phase (Figure 7). This morphology likely has a monoclinic unit cell containing four molecules of compound 1. Therefore, the unit volume of 497 Å is calculated from the indexed results. 3 This appears to be consistent with the anhydrous form. [Table 4] Substance D, metastable anhydride

[0248] Substance D of compound 1 is tentatively identified as an anhydrous form. Following a failed attempt to isolate amorphous compound 1 by rotational evaporation from DCM, only substance D was obtained as a mixture with morph A (and further unidentified peaks). Further unidentified peaks in the XRPD diffractogram were no longer clear after 7 weeks of storage at ambient conditions, but substance D remained (Figure 8). This suggests that substance D exhibits some degree of kinetic stability at ambient temperature. Nevertheless, substance D was shown to convert to morph A at ambient temperature in solvent-mediated experiments (see Example 4), confirming that substance D is metastable compared to morph A under those conditions.

[0249] Thermograms of substance D (as a mixture with form A) are shown in Figures 9A and 9B. TGA shows no weight loss up to 237°C, consistent with the mixture in its anhydrous form. DSC shows exothermic reaction, with decomposition beginning at around 174°C. Form E, metastable anhydride

[0250] Form E is the anhydrous form of compound 1, and decomposition begins at 201°C (Figures 12a and 12B). Form E is metastable compared to form A. The relative thermodynamic relationship was confirmed by interconversion slurry experiments conducted at ambient temperature, 55°C, and 77°C (see Example 4). Form E was most frequently observed due to the disproportionation of various salts of compound 1 in water. Crystals suitable for single-crystal X-ray diffraction were obtained by slowly cooling a THF solution saturated with amorphous compound 1.

[0251] The XRPD pattern and peak list for morphology E of compound 1 are illustrated in Figure 11 (experiment, top) and Table 5, respectively. [Table 5-1] [Table 5-2]

[0252] The single crystal structure of morphology E was successfully determined (Figure 10). The crystal system is monoclinic, and the space group is P21 / n. The lattice parameters and calculated volume are: a=11.83974(13)Å, b=23.5195(2)Å, c=14.48807(17)Å, α=90°, β=101.5333(11)°, γ=90°, V=3952.96(7)Å 3 The molecular weight is 438.89 gmol. -1 Therefore, Z=8, and the calculated density is 1.475 g / cm³. -3 The results were as follows. Further details of the crystal data and crystallographic data acquisition parameters are summarized in Table 6. The atomic displacement elliptic diagram of morphology E of compound 1 is shown in Figure 10. The shown asymmetric unit contains two molecules of compound 1. The calculated powder pattern is compared with the experimental pattern in Figure 11. [Table 6-1] [Table 6-2]

[0253] Thermograms of form E are shown in Figures 12A and 12B. The TGA shows no weight loss up to approximately 200°C, consistent with the anhydrous form. The DSC curve shows exothermic reaction, beginning at around 201°C, due to decomposition. hydrate form Hydrate of form F

[0254] Form F is likely the hydrate of compound 1. Form F was produced by forming a slurry of the HCl salt of compound 1 in water (see Example 2 and Table 1). The hydrate was shown to remain unchanged for 5 days under vacuum at ambient temperature, but dehydrated upon exposure to 100°C. Thermal characterization suggests that decomposition occurs immediately upon dehydration at high temperatures.

[0255] The XRPD patterns of the HCl salt of compound 1 and the hydrate of the free base form F are similar (Figure 13), suggesting that their crystal structures are also similar. The hydrate is derived from this structure as Cl - This is likely due to the displacement of the free base. Numerous attempts to directly crystallize the hydrate form from the free base have been unsuccessful, even with seed crystal additions of up to 50 wt%. Instead, the free base gel is thought to remain in the aqueous solvent system with high water activity, or eventually crystallize into form A with water activity of 0.7 or less. Therefore, the formation of the free base hydrate is unlikely to occur without an HCl salt as an intermediate.

[0256] The XRPD pattern and its peak list for morphology F of compound 1 are illustrated in Figure 14 and Table 7, respectively. The XRPD pattern was successfully indexed, providing strong evidence that it is representative of the single-crystal phase (Figure 14). This morphology likely has a triclinic unit cell containing two molecules of compound 1. Thus, the unit volume of the formula calculated from the indexed results is 511 Å. 3 This appears to correspond to a hydrate that can theoretically contain up to 1 mole of water per mole. [Table 7]

[0257] Solution 1 The 1H NMR spectrum matches the chemical structure of compound 1. Peaks that may be due to residual organic solvents are not evident. Ion chromatography shows negligible amounts of Cl, although these are due to the HCl salt. - The substance was quantified, and it was confirmed that morphology F is the crystalline form of the free base.

[0258] Thermograms of morphology F are presented in Figures 15A and 15B. TGA shows an initial weight loss of 3.2% up to 135°C, and a further loss of 0.8% from 135 to 187°C. Assuming water is the only volatile substance (residual organic solvents are discussed above). 1 (Not evident in the 1H NMR spectrum), the weight loss in the first step is equivalent to approximately 0.8 moles of water per mole of compound. The DSC curve shows broad endothermic dehydration, immediately resulting in exothermic reaction above 120°C. The exothermic DSC suggests that decomposition occurs immediately upon dehydration. Therefore, exposure of the sample to 100°C for several minutes results in loss of crystallinity by XRPD.

[0259] DVS isotherms demonstrate that morphology F exhibits limited hygroscopicity (Figure 16). A 1.8% weight increase is observed at 5–95% RH, and a 1.5% weight decrease with significant hysteresis is observed during desorption. The recovered DVS-treated sample was still morphology F by XRPD. Solvate form Morphological C-methanolate

[0260] Form C is a methanolate observed in experiments involving methanol. Specifically, amorphous compound 1 formed a slurry in a methanol solution under N2 conditions for 30 minutes at ambient temperature. Subsequent removal of the solvent at 60°C isolated Form C (Table 1). The solvate was shown to be kinetically stable, remaining unchanged for 9 weeks under ambient conditions. However, this methanolate desolvated to Form B (see Form B) upon overnight exposure to 80°C.

[0261] The XRPD pattern and its peak list for morphology F of compound 1 are illustrated in Figure 17 and Table 8, respectively. The XRPD pattern was successfully indexed, providing strong evidence that it is representative of the single-crystal phase (Figure 17). This morphology likely has a monoclinic unit cell containing four molecules of compound 1. Thus, the unit volume of the formula calculated from the indexed results is 544 Å. 3 This appears to correspond to a solvate that can theoretically accommodate up to 1 mole of methanol per mole. [Table 8]

[0262] Thermograms of form C are shown in Figures 18A and 18B. TGA shows a weight loss of 3.2% up to a maximum of 196°C. Assuming MeOH is the only volatile, this weight loss is equivalent to 0.5 moles of MeOH per mole of compound. In DSC, the broad endothermic reaction before 60°C is due to desolvation and transformation to form B. Exothermic reaction due to the desolvation of the desolvated form begins at 190°C. (Example 4) Relative thermodynamic stability

[0263] Interconversion experiments were performed to identify the most thermodynamically stable anhydrous form of compound 1 (Table 9). Interconversion or competitive slurry experiments are solution-mediated processes that provide a pathway for the growth of less soluble (more stable) crystals at the expense of more soluble crystalline forms. Apart from the formation or decomposition of solvates, thermodynamically stable polymorphs have lower energy and therefore lower solubility, so the more stable polymorphs obtained from interconversion experiments are independent of the solvent used. The choice of solvent affects the rate of polymorphic conversion, not the thermodynamic relationship between polymorphic forms. [Table 9]

[0264] Various combinations of forms B, E, F, and substance D were formed as slurries with form A at ambient and high temperatures (in experiments involving form E). Various solvent systems were used, resulting in varying water activity. Saturated solutions were prepared and then added to mixtures composed of approximately equal amounts of each form. This mixture was allowed to form a slurry for a specified period, the solid was harvested, and analyzed by XRPD.

[0265] Regardless of the mixture used, morphology A was dominant in each experiment. This suggests that morphology A is thermodynamically more stable than morphology B and substance D at ambient temperature, as well as more stable than morphology E at ambient temperature, 55°C, and 77°C. conclusion

[0266] Compound 1 has a weakly basic pK a Based on the values, stronger acids were selected for salt formation. Using all eight strong acids, crystalline substances were successfully isolated, and at least one representative crystalline sample was isolated from those identified as besylates, HCl salts, mesylates, napadisylates, napsylates, sulfates, and tosylates.

[0267] The free base form of compound 1, forms A, B, substance D, and E are anhydrous forms, form F is a hydrate, and form C is a methanelate. Anhydrous form A exhibits limited hygroscopicity, decomposition initiation at 207°C, and is identified as the thermodynamically most stable compared to the other anhydrous forms. The metastable desolvate of form B is obtained by desolvation of the methanelate of crystalline form C by exposure to 80°C overnight. The metastable anhydrous of form E was most frequently observed by disproportionation of various salts of compound 1 in water. The hydrate of form F was produced by slurry formation of HCl of form A, which is the HCl salt, in water. Although we do not wish to be bound by theory, the hydrate is derived from the crystalline structure of Cl - This is likely due to a displacement, which is unlikely to occur without the HCl salt as an intermediate. The hydrate was shown to remain unchanged for 5 days under vacuum at ambient temperature, but dehydration and decomposition occurred simultaneously upon exposure to 100°C. These experiments revealed that form A of compound 1 has superior stability compared to the other polymorphs examined. (Example 5) Effects of compound 1 in aged and disabled rats subject

[0268] Elderly male Long-Evans rats were obtained from Charles River Laboratories (Raleigh, NC) at 9 months of age and housed in a vivarium at Johns Hopkins University until background behavioral assessment in a water maze at 24 months of age. Younger rats from the same source were housed in the same vivarium and included in the background assessment at 6 months of age, but were not used for drug testing in the radial maze task. All rats were housed individually at 25°C and maintained in a 12-hour light / dark cycle. Unless otherwise specified, food and water were ad libitum. Rats were examined for health status and kept pathogen-free throughout the experiment and autopsy at the time of euthanasia. All procedures followed NIH guidelines using protocols approved by the Johns Hopkins University Institutional Animal Care Committee. Background behavioral assessment

[0269] All rats were screened using a standard assessment of spatial cognition before the start of drug studies. Background assessments were performed using the well-established Maurice water maze protocol, detailed elsewhere (Gallagher et al., 1993). Briefly, rats were trained for 8 days (3 trials per day) to locate a camouflaged escape platform located in the same place throughout the training in the water maze. Each of the 6 trials consisted of a probe trial (free swimming without an escape platform) that served to assess the development of the rats' exploratory ability to spatially locate the escape platform. During these probe trials, a learning index was generated from the rats' approaches to the escape platform and used to define impairment in older rats. The learning index was the sum of weighted approach scores obtained during the probe trials, with lower scores reflecting exploration closer to the escape platform and higher scores reflecting exploration further away from the platform (Gallagher et al., 1993). Cued training (visible escape platforms) was performed on the final day of training to test sensorimotor and motivational factors unrelated to spatial learning. Older rats with impaired spatial memory (i.e., rats with learning index scores outside the "normative" range of younger rats), but who performed well in cueed training, were used in the study described below. 1. Acute treatment of radial mazes with compound 1 using PO

[0270] In the radial maze task, various doses of compound 1 (GABA) A We tested hippocampus-dependent memory in fasted aged rats maintained at approximately 85% of their free-feeding weight under the influence of an α5 receptor agonist.

[0271] The radial maze device used consisted of eight equally spaced tracks. Elevated maze tracks (7 cm wide x 75 cm long) protruded from each side of an octagonal central platform (30 cm in diameter, 51.5 cm high). Transparent side walls on the tracks were 10 cm high and bent at a 65° angle to form indentations. Food wells (4 cm in diameter, 2 cm deep) were placed at the distal end of each track. Froot Loops (Kellogg Company) were used as rewards. Blocks (30 cm high x 12 cm wide) made of Plexiglas (trademark) could be placed to prevent entry into arbitrary tracks. Numerous additional maze cues were also provided around the device. Rats were initially subjected to pre-training (Chappell et al., 1998). The pre-training consisted of an acclimatization period, a training period for a standard win-shift task, another training period in which progressively longer delays were imposed while presenting a subset of tracks designated by the experimenter (five tracks open and three tracks blocked), and completion of an eight-track win-shift task (i.e., all eight tracks open).

[0272] During the acclimatization period, rats were accustomed to the maze in 10-minute sessions over several days. In each of these sessions, food rewards were scattered throughout the maze, first on the central platform and along the paths, and then gradually confined to the paths. After this acclimatization period, a standard training protocol was used, in which food pellets were placed at the end of each path. Rats underwent one trial daily. Each daily trial ended when all eight food pellets were obtained, or after 16 choices had been made, or after 10 minutes had elapsed. After this training period was completed, a second training period was conducted, in which the demands on memory were increased by imposing short delay times between trials. At the beginning of each trial, three paths of the eight-path maze were blocked off. Rats were able to obtain food from the five paths they were allowed to access during this initial "information phase" of the trial. Next, the rats were removed from the maze for progressively longer delays over several days (e.g., 1 minute, 30 minutes, 60 minutes), during which time the barriers on the maze were removed, allowing access to all eight paths. The rats were then returned to the central platform, where they were allowed to receive the remaining food rewards during the "remembering test" phase of the trial. The paths that were blocked and their arrangement were varied from trial to trial.

[0273] The number of errors made by rats during the memory test period was tallied. An error occurred in a trial if a rat entered a section of the run where food had already been retrieved in a component prior to the delay time, or if, in a session after the delay time, revisited a section it had already visited. After completing pre-training tests, rats were tested on tasks using different doses of compound 1 with a 5-hour memory retention delay between the information trial and the test trial.

[0274] The efficacy of compound 1 was tested using forced oral administration (PO), in which case the drug was administered at a volume of 10 ml / kg 30-40 minutes prior to each test. The tested doses were 0, 3, 10, and 30 mg / kg, using an ascending-descending dose series, i.e., a series of doses administered first in ascending order and then repeated in descending order. Thus, each dose was determined twice. The average number of errors made from the two determinations for each dose was used for analysis. Each drug test was conducted with washout days intervening every other day, and the vehicle used to deliver the drug was 20%Tween®-80.

[0275] The results demonstrate that aged, disabled rats treated with compound 1 at a dose of 10 mg / kg made fewer errors and successfully completed the radial maze (Figure 20). These results indicate that compound 1 improves cognition in aged, disabled rats. 2. Acute and chronic treatment of water mazes with compound 1

[0276] Rats were trained and tested in a new water maze environment to evaluate the effectiveness of this treatment. The water maze used here was housed in a different room and surrounded by curtains with a new set of patterns relative to the maze used for the initial assessment of cognitive state. The training and testing protocol used was the same as the spatial learning-activated protocol described by Haberman et al. (2008, Proceedings of the National Academy of Sciences USA, 105, 10601-10606). This task required rats to swim to a visible escape platform at a fixed location in the presence of spatial cues for eight training trials with an 8-minute interval between trials. One hour after the last training trial, rats were given a probe test in the absence of the escape platform (free swimming) to assess memory of the platform's location, measured by the time spent searching for the target location.

[0277] To evaluate the acute and chronic effects of treatment with compound 1, rats received drug injections for 15–16 days and were evaluated in a water maze for the first day (acute effect) and the last day (chronic effect) of treatment. Different ambient spatial cues and avoidance positions in the water maze were used for the initial and subsequent evaluations. Compound 1 was administered at a volume of 1 ml / kg using intraperitoneal injection (IP) at a dose of 10 mg / kg. On the day of the water maze evaluation, the drug was administered 30–40 minutes before the first training trial. The vehicle used to deliver compound 1 consisted of 10% N-methyl-2-pyrrolidone (NMP), 45% PEG-400, 11.25% 2-hydroxypropyl-β-cyclodextrin (HPCD) (25% concentration), and 33.75% distilled water.

[0278] The results demonstrate that rats treated with compound 1 at a dose of 10 mg / kg spent more time in the target quadrant of the Morris water maze (Figure 21). The results indicate that compound 1 improves cognition in aged, impaired rats. In one embodiment, for example, the following items are provided. (Item 1) structure [ka] A crystalline form of a compound having a crystalline form in which the crystalline form is form A. (Item 2) The crystal morphology according to item 1, wherein the crystal morphology exhibits an X-ray diffraction pattern (XRPD) including at least one peak selected from 3.0 and 21.0 degrees 2θ ± 0.2 degrees 2θ. (Item 3) The crystal morphology described in item 1, wherein the crystal morphology exhibits an X-ray diffraction pattern (XRPD) further comprising at least one additional peak selected from the group consisting of 9.1, 10.7, 13.8, 22.0, 23.1, 23.9, 24.4, and 27.1 degrees 2θ ± 0.2 degrees 2θ. (Item 4) The crystalline morphology described in item 1, characterized in essence by the X-ray powder diffraction (XRPD) pattern shown in Figure 5. (Item 5) The crystal morphology described in item 1, characterized by the X-ray diffraction space group of a C2 / c single crystal. (Item 6) Parameters: a=58.1415(14)Å, b=4.03974(8)Å, c=17.1204(3)Å, α=90°, β=90.261(2)°, γ=90°, V=4021.15(14)Å 3 The crystal morphology described in item 1, characterized by the X-ray diffraction unit cell of a single crystal having [a specific characteristic]. (Item 7) The crystal morphology described in item 1, which is essentially characterized by the differential scanning calorimetry (DSC) curve shown in Figure 3B. (Item 8) The crystalline morphology described in item 1, characterized by a differential scanning calorimetry (DSC) curve exhibiting exothermic properties starting at approximately 207°C. (Item 9) a. The X-ray powder diffraction (XRPD) pattern is essentially shown in Figure 5. b. X-ray diffraction space group of a single crystal of C2 / c, c. Parameters: a=58.1415(14)Å, b=4.03974(8)Å, c=17.1204(3)Å, α=90°, β=90.261(2)°, γ=90°, V=4021.15(14)Å 3 X-ray diffraction unit cell of a single crystal having d. The differential scanning calorimetry (DSC) curves shown in Figure 3B, and e. Differential scanning calorimetry (DSC) curves exhibiting exothermic properties starting at approximately 207°C. A crystalline form described in item 1, characterized by two or more of the following. (Item 10) structure

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Claims

1. structure 【Chemistry 14】 A crystalline compound having, wherein the crystalline is in anhydrous form A, The aforementioned anhydrous form A is (a) an X-ray diffraction pattern (XRPD) including peaks at 3.0, 9.1, 10.7, 21.0, and 24.4 degrees 2θ ± 0.2 degrees 2θ; and at least one additional peak selected from the group consisting of 13.8, 22.0, 23.1, 23.9, and 27.1 degrees 2θ ± 0.2 degrees 2θ; (b) X-ray diffraction space group of a C2 / c single crystal; (c) Parameters: a=58.1415(14)Å, b=4.03974(8)Å, c=17.1204(3)Å, α=90°, β=90.261(2)°, γ=90°, V=4021.15(14)Å ３ X-ray diffraction unit cell of a single crystal having; and (d) Differential scanning calorimetry (DSC) curve with exothermic properties starting at 207°C A crystal characterized by...

2. A pharmaceutical composition comprising crystals of the compound described in claim 1, and a pharmaceutically acceptable carrier.

3. a. The pharmaceutical composition according to claim 2, and b. One or more therapeutic agents selected from the group consisting of antipsychotics, memantine, SV2A inhibitors, and AChEIs, or one or more further pharmaceutical compositions comprising any of the pharmaceutically acceptable salts, hydrates, solvates, polymorphs, or prodrugs described above. A combination of pharmaceuticals, including [specific compound / product name].

4. A composition comprising crystals of the compound according to claim 1, a pharmaceutical composition according to claim 2, or a pharmaceutical combination according to claim 3, for treating cognitive impairment associated with CNS disorders.

5. The composition for use according to claim 4, wherein the CNS impairment is age-related cognitive impairment or mild cognitive impairment (MCI).

6. The composition for use according to claim 5, wherein the mild cognitive impairment (MCI) is amnesic mild cognitive impairment (aMCI).

7. The composition for use according to claim 4, wherein the CNS disorder is schizophrenia.

8. The composition for use according to claim 4, wherein the CNS disorder is Parkinson's disease.

9. A composition comprising crystals of the compound according to claim 1, a pharmaceutical composition according to claim 2, or a pharmaceutical combination according to claim 3, for treating Parkinson's disease psychiatric disorder.

10. A composition comprising crystals of the compound according to claim 1, a pharmaceutical composition according to claim 2, or a pharmaceutical combination according to claim 3, for treating brain cancer in a subject requiring treatment for brain cancer.

11. A method for producing the crystal described in claim 1, wherein the crystal is in anhydrous form A, and the method is a. The aforementioned structure 【Chemistry 19】 A compound having the above properties is dissolved in dichloromethane to form a solution. b. The step of evaporating the dichloromethane to produce a precipitate, and c. The step of recovering the precipitate to obtain the crystal, anhydrous form A. Methods that include...

12. A method for producing the crystal described in claim 1, wherein the crystal is in anhydrous form A, and the method is a. The aforementioned structure 【Chemistry 20】 A step of dissolving a compound having at a first temperature in a first solvent to produce a solution, b. A step of adding a second solvent to the solution to form a mixture. c. The step of cooling the mixture to a second temperature, and d. The step of collecting the obtained precipitate to obtain the crystal, anhydrous form A. Methods that include...

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